JP7187315B2 - Treatment of hepatitis delta virus infection - Google Patents

Description

The present invention provides methods for treating viral hepatitis caused by hepatitis delta virus (HDV) infection and relates to the fields of chemistry, medicinal chemistry, medicine, molecular biology and pharmacology.

Hepatitis delta virus (HDV) causes the most severe form of viral hepatitis and has no effective drug therapy (see Lau, 1999, Hepatology 30:546-549). HDV always presents as a co-infection with hepatitis B virus (HBV), and co-infected patients are much more likely to die from complications of the viral infection than those infected with HBV alone.

The HDV large delta antigen protein is mediated by prenyl lipid farnesyltransferase (see Glenn et al., 1992, Science 256:1331-1333; and Otto and Casey, 1996, J. Biol. Chem. 271:4569-4572). Contains the CXXX box (see Zhang and Casey, 1996, Annu. Rev. Biochem. 65:241-269) as an agent for prenylation. FTase-catalyzed protein farnesylation is an essential step in the processing of a wide variety of proteins, and involves the conversion of farnesyl diphosphate to cysteine in the protein's C-terminal tetrapeptide in a structural motif sometimes referred to as the CAAX box. It arises from the transfer of the farnesyl group of the acid. Furthermore, farnesylation is generally followed by post-translational modifications of farnesylated proteins, including proteolytic cleavage at the cysteine residue of the CAAX box and methylation of the cysteine carboxyl. Molecular genetic experiments have shown that specific mutations in the prenylation region in large delta-type antigens suppress both prenylation and HDV particle formation (Glenn et al., 1992, supra, Glenn et al., supra). 1998 J. Virol.72(11):9303-9306, Bordier et al., 2002 J. Virol.76(20):10465-10472). There is a continuing need for agents that treat HDV infection.

In one aspect, the invention provides methods for treating hepatitis delta virus (HDV) infection by oral administration of lonafarnib in combination with a CYP3A4 inhibitor (eg, ritonavir or cobicistat). In one aspect, the invention provides methods for treating HDV infection by oral administration of lonafarnib at a dose of about 25 mg BID or 50 mg BID in combination with administration of ritonavir at 100 mg BID or 100 mg QD. In one aspect, the present invention treats HDV infection by oral administration of lonafarnib at a dose of about 25 mg QD or BID, 50 mg QD or BID, 75 mg QD or BID in combination with QD or BID administration of ritonavir at a therapeutically effective amount. provide a method for In some embodiments, the invention further provides a therapeutically effective amount of an interferon (e.g., non-pegylated or pegylated interferon alpha or interferon lambda) in combination with QD or BID administration of ritonavir in a therapeutically effective amount. Oral administration of lonafarnib at a dose of about 25 mg QD or BID, 50 mg QD or BID, 75 mg QD or BID combined with QW administration at 100 mg QD or BID provides a method for treating HDV infection.

In another aspect, a method of reducing HDV viral load in a human patient is provided. In some embodiments, the method comprises treating the patient with lonafarnib-ritonavir co-therapy for at least 30 days. In some embodiments, the patient has chronic HDV infection. In some embodiments, the method comprises treating the patient with lonafarnib, ritonavir, and an interferon (eg, non-pegylated or pegylated interferon alpha or interferon lambda) for at least 30 days. In some embodiments, the method comprises treating the patient with lonafarnib-ritonavir co-therapy for at least 30 days, wherein the patient has a baseline viral load of at least ¹⁰ IU/mL serum prior to initiation of treatment. with treatment resulting in a reduction of viral load to less than 10 ³ IU/mL serum.

In some embodiments, the method comprises administering (eg, orally) lonafarnib at a daily dose in the range of 50 mg to 150 mg. In some embodiments, lonafarnib is administered at a daily dose of 50 mg. In some embodiments, lonafarnib is administered at a daily dose of 100 mg. In some embodiments, lonafarnib is administered at a dose of 25 mg BID. In some embodiments, lonafarnib is administered at a dose of 50 mg QD. In some embodiments, lonafarnib is administered at a dose of 50 mg BID. In some embodiments, lonafarnib is administered at a dose of 75 mg QD. In some embodiments, lonafarnib is administered at a dose of 75 mg BID.

In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 60 days. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least 90 days. In some embodiments, the patient is treated with lonafarnib-ritonavir co-therapy for at least one year.

In one embodiment, patients receiving lonafarnib-ritonavir co-treatment are administered daily doses of 50 mg/day to 150 mg/day, or daily doses of 50 mg/day to 100 mg/day, such as 25 mg/day, 50 mg/day , lonafarnib is administered at 75 mg/day or 100 mg/day, preferably each dose of lonafarnib is 75 mg or less, such as 25 mg or 50 mg, and ritonavir is administered at a daily dose of 100 mg/day to 200 mg/day; Preferably, each dose of ritonavir is 100 mg or less.

In one embodiment, the patient may be administered 75 mg lonafarnib BID and 100 mg ritonavir BID.

In one embodiment, the patient may be administered 50 mg lonafarnib BID and 100 mg ritonavir BID.

In one embodiment, the patient may be administered 25 mg lonafarnib BID and 100 mg ritonavir BID.

In one embodiment, patients may be administered 75 mg lonafarnib BID and 100 mg ritonavir QD.

In one embodiment, the patient is administered a daily dose of 100 mg lonafarnib and 200 mg ritonavir. For example, a patient may be administered 50 mg lonafarnib BID and 100 mg ritonavir BID.

In one embodiment, the patient is administered a daily dose of 75 mg lonafarnib and 100 mg ritonavir. For example, a patient may be administered 75 mg lonafarnib QD and 100 mg ritonavir QD.

In one embodiment, the patient is administered a daily dose of 50 mg lonafarnib and 100 mg ritonavir. For example, a patient may be administered 50 mg lonafarnib QD and 100 mg ritonavir QD.

In one embodiment, the patient is administered a daily dose of 50 mg lonafarnib and 200 mg ritonavir. For example, a patient may be administered 25 mg lonafarnib BID and 100 mg ritonavir BID.

In some embodiments, in the treatments described herein, lonafarnib and ritonavir are administered together in a single unit dosage form . In some embodiments, the unit dosage form comprises amorphous lonafarnib. In some embodiments, the unit dosage form comprises lonafarnib (eg, amorphous lonafarnib), ritonavir, and a copolymer. In some embodiments, the copolymer is povidone.

In some embodiments, in the treatments described herein, lonafarnib and ritonavir are administered as separate unit dosage forms at about the same time.

In some embodiments, in the treatments described herein, lonafarnib and ritonavir are administered together in a liquid formulation containing both lonafarnib and ritonavir.

In one embodiment, the patient is administered oral lonafarnib administered BID or QD at a dose of 50 mg/day, 75 mg/day, or 100 mg/day, and a daily dose of 100 mg/day BID or QD, e.g. Oral ritonavir administered daily. This treatment results in serum lonafarnib concentrations of greater than 2,000 ng/mL, preferably greater than 4,000 ng/mL, more preferably ranging from about 3,500 ng/mL to about 7,500 ng/mL.

In one embodiment, the patient is administered oral lonafarnib administered BID or QD at a daily dose of 50 mg/day, 75 mg/day, or 100 mg/day, optionally with a boosting agent. This treatment results in serum lonafarnib concentrations of greater than 2,000 ng/mL, preferably greater than 4,000 ng/mL, more preferably ranging from about 3,500 ng/mL to about 7,500 ng/mL.

In some embodiments, the patient has a baseline viral load of at least 10 ⁴ HDV RNA copies/mL serum prior to treatment and treatment results in a viral load of less than 10 ² HDV RNA copies/mL serum. In some embodiments, the patient has a baseline viral load of at least 10 ⁷ HDV RNA copies per mL serum prior to treatment and treatment results in a viral load of less than 10 ⁵ HDV RNA copies per mL serum.

In some embodiments, the treatment results in a viral load of less than 10 ² HDV RNA copies per mL serum, the patient receives an additional course of treatment of lonafarnib-ritonavir co-therapy for 30 days, and the viral load is It remains below 10 ² HDV RNA copies per mL of serum afterwards.

In some embodiments, the treatment further comprises administering interferon. In some embodiments, the interferon is interferon alpha or interferon lambda. In some embodiments, the interferon is pegylated interferon. In some embodiments, the interferon is pegylated interferon alpha-2a or pegylated interferon lambda-1a.

In some embodiments, lonafarnib and ritonavir or a similar potentiator, optionally in combination with interferon, for at least 30 days, more often at least 60 days or at least 90 days, even more often at least 120 days, Patients are administered a course of treatment, sometimes for at least 150 days, and sometimes for at least 180 days. In some embodiments, lonafarnib and ritonavir or a similar potentiator is administered to the patient during a course of treatment spanning at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or longer. administered to In some embodiments, administration is discontinued after viral levels have fallen below 3 log HDV RNA copies/mL (less than 1,000 copies/mL) or below levels of detection for a period of time (such as 1-3 months or longer). .

In some embodiments, the treatments disclosed herein result in HDV RNA levels of less than 1,000 copies/mL serum or less than 1,000 IU/mL serum, and in some cases It can remain at a low level for at least one month. In some embodiments, lonafarnib-ritonavir co-treatment is continued after HDV RNA levels are determined to be below a threshold level (e.g., below 1,000 copies/mL serum or below 1,000 IU/mL serum). be.

In some embodiments, the treatments disclosed herein result in HDV RNA levels of less than 100 copies/mL serum or less than 100 IU/mL serum, and in some cases for at least 1 month It can remain at a low level. In some embodiments, lonafarnib-ritonavir co-treatment is continued after HDV RNA levels are determined to be below a threshold level (eg, below 100 copies/mL serum or below 100 IU/mL serum).

In some embodiments, therapeutic approaches disclosed herein result in HDV RNA levels that are below the level of detection, and in some cases may remain at low levels for at least one month. In some embodiments, lonafarnib-ritonavir co-treatment is continued after the HDV RNA level is determined to be below a threshold level (eg, below the level of detection).

In some embodiments, the patient has a baseline viral load of at least 10 ⁵ HDV RNA copies per mL serum prior to initiation of treatment and treatment reduces the viral load to less than 10 ² HDV RNA copies per mL serum. resulting in a decrease in

In some embodiments, the patient has a baseline viral load of at least 10 ⁵ IU/mL serum prior to initiation of treatment, and treatment results in a decrease in viral load to 10 ² IU/mL serum.

In some embodiments, after the patient is determined to have a viral load of less than 10 ² HDV RNA copies per mL serum (alternatively less than 10 ² IU/mL serum), lonafarnib-ritonavir-co-treatment is administered at least 30 continue for days.

In some embodiments, the patient has a baseline viral load of at least 10 ⁷ HDV RNA copies per mL serum (alternatively less than 10 ⁷ IU/mL serum) prior to initiation of treatment and treatment is Generates a viral load of less than 10 ⁵ HDV RNA copies per serum (alternatively less than 10 ⁵ IU/mL serum).

In some embodiments, the therapeutic regimens disclosed herein comprise administering lonafarnib at a first dose followed by administering lonafarnib at a second dose, wherein the second dose is lower than dose. In some embodiments, a therapeutic regimen disclosed herein administers lonafarnib at a first dose during a first treatment period, and then at a higher dose than the first dose during a second treatment period. An escalating dosing regimen comprising administering a second dose of lonafarnib. In some embodiments, the patient is administered lonafarnib at a first dose of 25 mg BID during a first treatment period, followed by lonafarnib at a second dose of 50 mg BID during a second treatment period. In some embodiments, the therapeutic regimen comprises administering lonafarnib at a first dose during a first treatment period, followed by a second dose if the patient does not experience unacceptable gastrointestinal side effects during the first treatment period. or administering lonafarnib at the first dose during the first treatment period and then administering lonafarnib at the first dose for the first treatment period and then administering a second dose of lonafarnib that is lower than the first dose during a second treatment period if a non-performing gastrointestinal side effect is experienced.

In another aspect, methods are provided for inducing immune reactivation in patients infected with HDV and HBV. In some embodiments, the method comprises administering lonafarnib at a total daily dose in the range of 50 mg to 150 mg for at least 12 weeks and/or until a hepatitis flare is observed. In some embodiments, the hepatitis flare is accompanied by a transient increase in the patient's HBV viral load. In some embodiments, the method comprises administering a lonafarnib-ritonavir co-treatment in which ritonavir is administered at a total daily dose of 100-200 mg. After immune reactivation, HDV viral load can be reduced by at least 3 logs, by at least 2 logs, or reduced to undetectable levels.

In one embodiment, inducing immune reactivation in a patient infected with HDV and HBV comprises administering lonafarnib at a first dose followed by administering lonafarnib at a second dose; The dose is lower than the first dose. For example, in some cases, a first dose is administered for at least 8 weeks, a second dose is administered for at least 2 weeks, and optionally at least 4 weeks. In some cases, the first dose of lonafarnib is 50 mg BID and the second dose of lonafarnib is 50 mg QD. In some cases, a first dose of lonafarnib and a second dose of lonafarnib are administered in combination with ritonavir at a dose of 100 mg BID.

In another embodiment, the lonafarnib-ritonavir co-therapy described herein is discontinued after a treatment period of 10-24 weeks, and the patient is not administered lonafarnib-ritonavir co-therapy for at least 4 weeks. In some embodiments, lonafarnib-ritonavir co-therapy is discontinued after a treatment period of 10-14 weeks, or lonafarnib-britonavir co-therapy is discontinued after 12 weeks of treatment.

In some embodiments, a therapeutic approach disclosed herein comprises detecting the occurrence of a hepatitis flare and/or a transient increase in the patient's hepatitis B virus (HBV) viral load of at least 3 logs. detecting an increase in In some embodiments, hepatitis flare is characterized by an acute elevation of serum alanine aminotransferase (ALT) to levels above 200 U/L. In some embodiments, hepatitis flare is characterized by an acute elevation of serum alanine aminotransferase (ALT) to levels above 800 U/L. In some embodiments, treatment is discontinued within 25 weeks (eg, within 20 weeks or within 12 weeks) after the hepatitis flare. In some embodiments, treatment is discontinued at 12 weeks of treatment. In some embodiments, therapy is discontinued after 10-14 weeks of treatment. In some embodiments, treatment is discontinued after a treatment period (e.g., after a 10-24 week treatment period, after a 10-14 week treatment period, or after a 12 week treatment period) and treatment (e.g., after a 12-week treatment period) The lonafarnib britonavir co-treatment) is not administered to the patient for at least 4 weeks, such as at least 8 weeks, at least 12 weeks, or longer. In some embodiments, treatment is discontinued prior to detecting the onset of hepatitis flare and/or prior to detecting a transient increase.

In yet another aspect, methods of reducing HBV viral load in patients infected with HBV and HDV are provided. In some embodiments, the patient has a chronic HBV infection and the course of treatment results in a decrease in the patient's HBV viral load compared to baseline levels at the start of treatment. In one approach, the method comprises administering lonafarnib at a total daily dose ranging from 50 mg to 150 mg for at least 12 weeks, optionally administering lonafarnib and ritonavir, and detecting at least a 1 log reduction in HBV viral load. including. In some cases, treatment results in at least a 2-log reduction in HBV viral load. In some cases, the patient has not been treated with an antiviral nucleotide or nucleoside analogue. In some embodiments, the patient is also treated by administration of interferon, which may be pegylated interferon lambda, which may be administered at a dose of 120 mcg QW or 180 mcg QW.

In yet another aspect, a method of reducing the viral load of hepatitis delta virus (HDV) in a human patient with chronic HDV infection is provided, wherein the patient receives lonafarnib-interferon co-treatment for at least 30 days, wherein Co-treatment includes oral administration of lonafarnib in a total daily dose ranging from 50 mg to 150 mg, and oral interferon lambda-1a in a total weekly dose ranging from 120 mcg to 180 mcg. Exemplary lonafarnib doses are 25 mg BID and 50 mg BID. In certain embodiments, the interferon lambda-1a is pegylated interferon lambda-1a.

In one aspect, prior to initiation of oral administration of lonafarnib and ritonavir, the patient receives at least one GI modifying agent, and typically a combination of at least two GI modifying agents (antiemetic, antidiarrheal and one or more of antacids) are treated prophylactically.

In another aspect, the GI modifying drug is administered simultaneously with lonafarnib and ritonavir, and lonafarnib is administered as a delayed release formulation and is not released until after the GI modifying drug begins to take effect.

In yet another aspect, a unit dosage form is provided comprising lonafarnib and ritonavir. In some embodiments, a unit dosage form is formulated for oral administration. In some embodiments, the unit dosage form comprises lonafarnib and ritonavir in a ratio of about 1:2 (w/w) or about 1:4 (w/w), and the unit dosage form is formulated for oral administration. be done. In some embodiments, the unit dosage form comprises lonafarnib in an amount of about 25 mg to about 100 mg and ritonavir in an amount of about 50 mg to about 100 mg. In some embodiments, the unit dosage form comprises amorphous lonafarnib. In some embodiments, the unit dosage form comprises 25 mg amorphous lonafarnib and 100 mg ritonavir. In some embodiments, the unit dosage form comprises 50 mg amorphous lonafarnib and 100 mg ritonavir. In some embodiments, the unit dosage form comprises a mixture, multiparticulate formulation, or bilayer formulation of lonafarnib and ritonavir. In some embodiments, the unit dosage form further comprises a copolymer. In some embodiments, the copolymer is selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose phthalate, polyvinylpyrrolidone-vinyl acetate copolymer, hypromellose-acetate-succinate, and mixtures thereof. In some embodiments, the copolymer is not povidone. In some embodiments, the copolymer is povidone. In some embodiments, the povidone is povidone K30. In some embodiments, the unit dosage form is formulated as a capsule or tablet. In some embodiments, one or both of lonafarnib and ritonavir are formulated for immediate release. In some embodiments, one or both of lonafarnib and ritonavir are formulated for controlled release.

In another aspect, a liquid formulation is provided comprising lonafarnib and ritonavir. In some embodiments, the liquid formulation comprises lonafarnib and ritonavir in a 1:4 or 1:2 ratio.

In yet another aspect, a pharmaceutical package is provided comprising lonafarnib and ritonavir in unit dosage form .

These and other aspects and embodiments of the invention are described in more detail below.

Time course of HDV RNA levels (copies/mL) in patients treated with 100 mg lonafarnib BID for 28 days. See Example 1.

Figure 3. Change in HDV RNA viral load versus lonafarnib serum levels in patients treated with 100 mg lonafarnib BID for 28 days. See Example 1.

HDV RNA viral titers in human patients treated with either 200 mg BID or 300 mg BID doses of lonafarnib for 28 days. See Example 2.

Change in HDV RNA viral titers in patients treated with lonafarnib and interferon (Pegasys) at doses described in Example 3. FIG.

HDV RNA viral titers in patients treated with 100 mg BID dose of lonafarnib and 100 mg QD of ritonavir for 28 days. See Example 4.

Change in HDV RNA virus titers. 6A graphically depicts the change in HDV RNA viral titers from standardized baseline in patients treated for 28 days with lonafarnib and ritonavir at doses described in Example 5. FIG. 6B graphically depicts changes in HDV RNA viral titers in patients treated with lonafarnib and ritonavir at doses described in Example 5 for 56 days. 6C graphically depicts changes in HDV RNA viral titers in patients treated for 84 days with lonafarnib and ritonavir at doses described in Example 5. FIG.

Inverse correlation between higher lonafarnib serum levels and HDV viral load in patients receiving 100 mg lonafarnib BID and 100 mg ritonavir QD.

Decreased correlation between lower lonafarnib serum levels and HDV viral load in patients receiving 150 mg lonafarnib QD and 100 mg ritonavir QD.

Relationship between lonafarnib serum concentration and change in viral load in patients receiving 100 mg lonafarnib BID and 100 mg ritonavir QD.

Change in HDV RNA viral titers in patients treated with lonafarnib and pegylated interferon or lonafarnib and ritonavir.

Changes in ALT values in patients treated with lonafarnib and pegylated interferon.

Change in HDV RNA viral titers in patients treated with lonafarnib, ritonavir and interferon using the combinations, doses and schedules described in Example 6.

FIG. 10 is the change in HDV RNA viral titers in patients treated with lonafarnib, ritonavir and interferon using the combinations, doses and schedules described in Example 7. FIG.

Change in HDV RNA viral titers in patients treated with lonafarnib, ritonavir and interferon using the combinations, doses and schedules described in Example 8.

Changes in HDV RNA viral titers in patients treated with lonafarnib-ritonavir co-therapy with or without pegylated interferon-α, as described in Example 12. FIG. (A) Changes in HDV RNA virus titers measured after 4 weeks. (B) Changes in HDV RNA virus titers measured after 8 weeks.

Changes in HDV RNA virus titers at various time points in patients treated with lonafarnib-ritonavir co-therapy with or without pegylated interferon-α, as described in Example 12. FIG.

FIG. 12 is the time course of HDV RNA levels (copies/mL) in patients treated with 50 mg BID lonafarnib and 100 mg BID ritonavir, as described in Example 12. FIG.

FIG. 12 is the time course of HDV RNA levels (copies/mL) in patients treated with 50 mg BID lonafarnib, 100 mg BID ritonavir, and 180 mcg QW pegylated interferon-α, as described in Example 12. FIG.

FIG. 10 is the time course of HDV RNA levels (copies/mL) in patients treated with 25 mg BID lonafarnib and 100 mg BID ritonavir, as described in Example 12. FIG.

FIG. 4 is a time course of HDV RNA levels (copies/mL) in patients treated with 25 mg BID lonafarnib, 100 mg BID ritonavir, and 180 mcg QW pegylated interferon-α, as described in Example 12. FIG.

12 is the change in ALT values at week 12 of treatment, as described in Example 12. FIG.

Titrating regimen with 24 weeks of treatment for lonafarnib/ritonavir co-treatment, as described in Example 14. No adjustment for ritonavir was shown.

Change in HDV RNA viral titers in patients treated with lonafarnib and ritonavir using the combinations, doses and schedules described in Example 14.

FIG. 10 is the time course of HDV RNA levels (copies/mL) and ALT levels (U/L) in patients treated with lonafarnib/ritonavir co-therapy, as described in Example 14. FIG.

24 is the change in ALT values at 24 weeks of treatment, as described in Example 14. FIG.

Post-treatment ALT flare of patient A-001-5 treated with 200 mg BID lonafarnib as described in Example 15, showing HDV-RNA negativity and ALT normalization after suppression of ALT flare and HDV RNA and HBV DNA. In Figures 26-30, the limit of quantitation (LOQ) for the HDV assay is 3.2 log IU/mL and the LOQ for the HBV assay is 2 log IU/mL. Thus, for HDV, measurements graphed as >0 log and <3.2 log are considered to indicate the presence of HDV at concentrations greater than 0 IU/mL and less than 3.2 loguL/mL, although within this range It does not indicate an exact amount. Similarly, for HBV, measurements graphed as >0 log and <2 log are considered to indicate the presence of HBV at concentrations greater than 0 IU/mL and less than 2 log IU/mL, although accurate amounts within this range are considered. does not indicate

FIG. 11 is a post-treatment ALT flare of patient A-001-1 treated with 300 mg BID lonafarnib as described in Example 15 showing HDV-RNA negativity and ALT normalization after ALT flare and suppression of HDV RNA and HBV DNA.

100 mg BID lonafarnib in combination with 50 mg BID ritonavir for about 10 weeks followed by lonafarnib (150 mg QD) and Post-treatment ALT flare in patient A-002-3 treated with ritonavir (50 mg BID) for 2 weeks.

75 mg BID lonafarnib in combination with 100 mg BID ritonavir over weeks 1-12 to 50 mg BID lonafarnib in combination with 100 mg BID ritonavir showing reduction of HDV-RNA and ALT after suppression of ALT flare and HDV RNA and HBV DNA as described in Example 15. Post-treatment ALT flare in patient A-002-14 treated from 13-24 weeks and with pegylated interferon-alpha from 16-24 weeks.

Post-treatment ALT flare of patient A-002-23 treated with 50 mg BID lonafarnib in combination with 100 mg BID ritonavir as described in Example 15, showing ALT flare and HDV-RNA negativity and ALT normalization after suppression of HDV RNA and HBV DNA. is.

Ritonavir at ratios of 1:1:2 (w/w), 1:2:3 (w/w), and 1:1:5 (w/w) prepared as described in Example 16- 1 is a characteristic X-ray powder diffraction (XRPD) pattern of a lonafarnib-povidone composition.

Thermogravimetric analysis. (A) Ritonavir-povidone (1:1) and ritonavir-lonafarnib-povidone (1:1:2), (1:2:3) and (1:1:5) prepared as described in Example 16 ) is a characteristic powder TGA thermogram of the co-precipitate. (B) Characteristic powders comparing ritonavir-lonafarnib-povidone (1:1:2) and ritonavir-lonafarnib-HPMC (1:1:2) co-precipitates prepared as described in Example 16. TGA thermogram.

This detailed description of the invention is divided into sections for the convenience of the reader. As will be apparent to one of ordinary skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein may be replaced by separate components and, without departing from the scope or spirit of this disclosure, Other embodiments have features that are easily separated or combined with features of any of the other embodiments (whether described in the same or different sections of this disclosure). Any recited method can be performed in the order of events recited or in any other order that is theoretically possible. Embodiments of the present disclosure employ techniques such as synthetic organic chemistry, biochemistry, biology, molecular biology, recombinant DNA techniques, pharmacology, etc., that are within the skill of the art, unless otherwise noted. Such techniques are explained fully in the literature. This disclosure is not limited to particular embodiments described, and actual embodiments of the invention may, of course, differ from those described herein.

I. DEFINITIONS The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the present invention is limited only by the appended claims. do not have. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Throughout this specification and the claims that follow, reference is made to a number of terms that are to be defined with the following meanings unless the intent to the contrary is clear. In some cases, terms having commonly understood meanings are defined herein for clarity and/or for immediate reference, and that such definitions are encompassed herein are recognized in the art. should not be construed as representing an essential difference from the definitions of terms commonly understood in

Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods, devices and materials are described herein. All technical and patent documents cited herein are hereby incorporated by reference in their entirety. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such disclosure by virtue of prior invention.

All numerical designations including ranges such as pH, temperature, time, concentration and molecular weight are approximations varying (+) or (-) in increments of 0.1 or 1.0 as appropriate. All numerical designations should be understood to be preceded by the term "about," even if not necessarily explicitly indicated.

HDV levels are generally presented using log ₁₀ units, in accordance with normal practice in virology. HDV RNA levels can be presented in units of "RNA copies per mL" or "International Units (IU) per mL". Chudy et al. WHO Expert Committee on Biological Standardization WHO/BS/2013.2227. . Both units are used herein. As used herein, the description of "HDV RNA copies per mL" (not including discussion related to clinical trial results, e.g., as shown in the Examples) is for descriptive or foundational purposes. , should be read as "HDV RNA copies/mL or HDVIU/mL". Where specific amounts of HDV RNA copies per mL are stated, a multiplier of 1.2 is applied to convert amounts of HDV RNA copies/mL to amounts of IU/mL for description and support of the specification. can do. For example, "120 HDV RNA copies per mL" should be read as "120 copies/mL or 100 IU/mL".

HBV DNA levels were estimated using the IU rule (see Saldanha et al., 2001, International Health Organization International Collaboration to Establish International Standards for Hepatitis B Virus DNA Nucleic Acid Amplification Techniques, VoxSanguinis 80(1) 63-71). generally described in the technical field.

Changes in HDV RNA levels can be expressed as a "log reduction" following normal practice in virology. For example, a 1 log reduction in viral load (i.e. -1 log) (e.g. 7 log to 6 log) is a 10-fold reduction and a 2 log reduction in viral load (i.e. -2 log) is , a 100-fold reduction. A decrease from 7 log RNA copies/mL to 6 log RNA copies/mL is equivalent to a decrease from 7 log IU/mL to 6 log IU/mL. Alterations in HBV DNA levels can be described using the same terms.

The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes plural compounds.

The term "administering" refers to introducing a compound, composition or agent of this disclosure to a host, such as a human. One preferred route of administration of the drug is oral administration. Other routes are intravenous and subcutaneous administration.

"Antidiarrheals" can be of one of two types: those that thicken stool and those that slow intestinal spasms. Stool-thickening compounds (such as psyllium) absorb water. This helps clump the stool and make it firmer. Antispasmodic antidiarrheal preparations slow intestinal spasms by acting on μ-opioid receptors in the intersegmental plexus of the large intestine. By reducing the activity of the enteric plexus, this in turn reduces the tone of the longitudinal and circular smooth muscles of the intestinal wall, increasing the time the substance stays in the intestinal tract and absorbing more water from the faeces. make it possible to Anticonvulsants also decrease colonic mass movements and suppress the gastrocolic reflex.

The term "antacid" refers to agents that reduce or lessen the effects of gastric acid secretion and includes H2-receptor antagonists and proton pump inhibitors.

The term "baseline" refers to measurements (e.g., of viral load, patient status, ALT levels) taken prior to a course of treatment, unless otherwise specified or clear from context.

The terms "BID" (twice a day), "QD" (once a day), "QW" (once a week), etc. have their usual meanings in the medical arts.

The term "comprising" is intended to mean that the compounds, compositions and methods are inclusive of the recited elements, but not excluding others. "consisting essentially of, when used to define compounds, compositions and methods other elements that will materially affect the basic and novel characteristics of the claimed invention shall mean the exclusion of "Consisting of" shall mean excluding any element, step or ingredient not specified in the claim. Embodiments defined by each of these transitional phrases are within the scope of this invention.

The terms "course of treatment" and "course of treatment" are used interchangeably herein and refer to medical intervention after a patient has been diagnosed, eg, when infected with HDV and requiring medical intervention. Medical intervention includes, but is not limited to, administration of drugs for a period of time, typically at least one month, months, or months or years for an HDV-infected patient.

The term "GI intolerance" refers to any one of diarrhea, nausea and vomiting individually or in combination.

The terms "hepatitis flare", "ALT flare" and "immune reactivation" are used interchangeably and describe an acute elevation of serum alanine aminotransferase (ALT) to levels greater than double the baseline ALT in hepatitis patients point to In some embodiments, a hepatitis flare is characterized by an acute elevation of serum ALT to levels greater than 5 times the upper limit of normal (ULN). In some cases, serum ALT levels are greater than or equal to 200 U/L. See Liaw, Journal of Gastroenterology and Hepatology, 2003, 18:246-252. Methods for measuring serum ALT levels are known in the art. For example, J. Clin. Chem. Clin. Biochem. , 1986, 24:481-495. In some embodiments, hepatitis flare may be therapeutic in HDV patients receiving treatment with lonafarnib.

The term "HDV RNA viral load" or "viral load" of a human serum or plasma sample refers to the amount of HDV RNA in a given amount of human serum or plasma sample. HDV RNA is commonly detected by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) assays. In such assays, the amount of signal produced during the assay is proportional to the amount of HDV RNA in the sample. The signal from the test sample is compared to the signal of the quantified Hepatitis Delta RNA standard dilution series, and the copy number of the genome copy is calculated. For example, Kodani et al. , 2013, J.P. Virol. Methods, 193(2), 531; Karatayli et al. , 2014, J.P. Clin. See Virol, 60(1), 11. HDV RNA viral load can be reported using RNA copies per mL serum (or plasma) or International Units (IU) per mL serum (or plasma) (Chudy et al, 2013, supra). Commercial assays are available from ARUP Laboratories (Salt Lake City, UT). The detection limit of the ARUP HDV RNA assay is reported to be 31 IU/mL. Analytik Jena AG (Germany) offers the RoboGene® HDV RNA Quantification Kit 2.0, CE-IVD certified to WHO standards, to assess response to antiviral therapy. The detection limit of the RoboGene® assay is reported to be 6 IU/mL. A "viral load" without a specific unit (eg, "a viral load less than 100") refers to copies of HDV RNA per mL of serum, unless otherwise indicated or clear from context. References to below the level of detection mean below 6 IU/mL unless otherwise specified.

The term "HDV infection" with respect to humans (the host) refers to the fact that the host suffers from an HDV infection. Typically, an HDV-infected human host has at least about 2 log HDV RNA copies per mL of host serum or plasma, or 10 ² copies of HDV-RNA per mL of host serum or plasma, often at least about 3 log HDV per mL of host serum or plasma. RNA copies, or 10 ³ copies of HDV-RNA per mL of host serum or plasma, and often at least about 4 log HDV RNA copies per mL of host serum or plasma, or host serum, especially for patients not receiving any treatment. or 10 ⁴ copies of HDV-RNA per mL of plasma, e.g., about 4 log HDV RNA copies per mL of host serum or plasma to 8 log HDV RNA copies per mL of host serum or plasma, or 10 ⁴ -10 HDV-RNA per mL of host serum or plasma. It has an HDV RNA viral load such as ⁸ copies. As used herein, the term "chronic HDV infection" with respect to a human host is defined as having been infected for at least 6 months as described by a positive HDV antibody (Ab) test and/or detectable by qRT-PCR. , refers to persistent HDV infection in human hosts. Diagnosis and pathogenesis of HDV are described, for example, in Wedemeyer et al. , Nat. Rev. Gastroenterol. Hepatol, 2010, 7:31-40.

The term "HBV infection" refers to hepatitis B (HBV) infection. It will be understood by those skilled in the art that HDV infection can only occur in individuals who are also infected with HBV. Thus, human hosts with HDV infection also have HBV infection. Diagnosis of HBV infection can be based on the presence of HBV serological markers such as hepatitis B surface antigen (HBsAg), hepatitis B core IgM antibodies (anti-HBc IgM), and/or the presence of HBV DNA. HBV serological markers and methods of detecting and quantifying HBV DNA have been described in the art. For example, Liu et al. , 2015, World J Gastroenterol 21:11954-11963. In some embodiments, a human host with HDV infection and HBV infection has an HBV viral load of at least about 2 log HBV DNA copies/mL host serum or plasma, or 10 ² copies of HBV-DNA/mL host serum or plasma. and often at least about 3 log HBV DNA copies/mL host serum or plasma, or 10 ³ copies of HBV-DNA/mL host serum or plasma, or at least about 4 log HBV DNA copies/mL host serum or plasma, or 10 ⁴ copies HBV-DNA/mL host serum or plasma viral load.

The term "HBV viral load" of a human serum or plasma sample refers to the copy number of human HBV DNA in a given amount of human serum or plasma sample. Real-time PCR can be used to detect and quantify HBV DNA. Commercial assays are available for quantifying HBV DNA. In the United States, Abbott offers the Real-Time HBV Assay, an in vitro PCR assay for the quantification of HBV DNA in human serum or plasma. A CE certified kit for real-time PCR-based detection of HBV is commercially available from Analytik Jena, Germany (RoboGene® HBV DNA Quantification Kit 2.0).

"H2-receptor antagonists" are a class of drugs used in the stomach to block the action of histamine on parietal cells (specifically histamine H2 receptors) and reduce the production of acid by these cells. be. H2 antagonists are used to treat dyspepsia.

A "5-HT3 antagonist" is a subtype of serotonin receptor found in several key sites involved in vomiting, including the vagal afferents, the nucleus tractus solitarius (STN) and the area postrema itself. - A class of drugs that act as receptor antagonists at the HT3 receptor. 5-HT3 receptor antagonists suppress vomiting and nausea by inhibiting serotonin binding to 5-HT3 receptors.

The term "lonafarnib" or "LNF" or "EBP994", also known by the trade name Sarasar (Schering), has the structural formula shown below, FTase inhibitor 4 (2[4-[(11R)-3, 10-dibromo-8-chloro-6,11-dihydro-5H benzo[5,6]-cyclohepta[1,2b]pyridin-11yl]-piperidino]-2-oxoethyl]-1-piperidinecarboxamide) (Sch- 66336 or SCH 66336).

Lonafarnib is a crystalline solid with a melting point of approximately 200° C. and is non-hygroscopic. Its molecular weight is 638.7. In the solid state, this compound is thermally stable. In solution, lonafarnib is stable at neutral pH, but is hydrolyzed under acidic or basic conditions. Lonafarnib is a poorly water soluble tricyclic compound that produces low and variable bioavailability in animals when formulated in crystalline form. Considerable efforts have been directed to formulation development to improve oral bioavailability. In addition to the drug substance, suitable pharmaceutical formulations of lonafarnib for administration in capsules contain povidone, poloxamer 188, croscarmellose sodium, silicon dioxide and magnesium stearate. The product is formulated with a drug:povidone (1:1) co-precipitate to achieve optimal bioavailability. These are safe and well-tested excipients commonly used in commercial products.

If the amount of HDV RNA per mL of serum or plasma is below the detection limit of the assay used (i.e., qRT-PCR), the patient is "HDV-RNA negative," or equivalently "HDV clear." assay). The amount of HDV RNA per mL of serum or plasma is below the limit of detection in a single viral load determination followed by at least 6 weeks, at least 12 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, or at least 1 year A patient is considered "persistently HDV-RNA-negative" if viral load determinations or measurements taken over an extended period of time, such as, remain below the limit of detection. Unless otherwise specified, patients will be assessed for "persistent HDV-RNA considered to be “negative”. It is understood that measurements obtained from serum samples may not detect the presence of low levels of virus in hepatocytes (“reservoirs”). In many cases the presence of low levels does not cause any symptoms. In some instances, reservoir virus populations expand and patients relapse and require further treatment.

"NK1" is a G protein-coupled receptor located in the central and peripheral nervous system. This receptor has a dominant ligand known as substance P (SP). SP is a neuropeptide composed of 11 amino acids that sends and receives impulses and messages from the brain. It is found in high concentrations in the vomiting center of the brain and causes vomiting regurgitation when activated. NK-1 receptor antagonists block the signal emitted by the NK1 receptor.

The term "oral dosage form" as used herein refers to dosage forms suitable for oral administration such as tablets, capsules, gel capsules, syrups, elixirs and suspensions. "Solid oral dosage forms" include tablets, capsules, caplets, and the like.

The term "oral unit dosage form," as used herein, refers to a unit dosage form intended for oral administration.

The terms "patient," "host," or "subject" are used interchangeably and refer to a human infected with HDV, including patients previously infected with HDV and cleared of the virus.

The term "pharmaceutical composition" is meant to encompass compositions suitable for administration to a subject. Generally, a "pharmaceutical composition" is preferably sterile and free of contaminants that may elicit an undesired reaction in a subject (e.g., one or more compounds in the pharmaceutical composition are of pharmaceutical grade). Pharmaceutical compositions can be administered to a subject or patient in need thereof by many different routes of administration, including oral, intravenous, buccal, rectal, parenteral, intraperitoneal, intradermal, intratracheal, intramuscular, subcutaneous, inhalation, and the like. can be designed for administration to

The terms "pharmacologically acceptable excipient", "pharmacologically acceptable diluent", "pharmacologically acceptable carrier" or "pharmacologically acceptable adjuvant" are generally means excipients, diluents, carriers and/or adjuvants useful in preparing pharmaceutical compositions that are safe, non-toxic, and not otherwise biologically undesirable; and/or excipients, diluents, carriers and adjuvants acceptable for human pharmaceutical use. A "pharmaceutically acceptable excipient, diluent, carrier and/or adjuvant" as used in the specification and claims includes one or more of such excipients, diluents, carriers and adjuvants. A wide variety of pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents, and adjuvants such as pH adjusting and buffering agents, tonicity agents, stabilizers, wetting agents and the like are useful in the present technology. known in the field. Pharmaceutically acceptable excipients have been extensively described in various publications; Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, &Wilkins; C. Ansel et al. , eds. , 7th ed. , Lippincott, Williams, &Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.M. H. Kibbe et al. , eds. , 3rd ed. Amer. Includes Pharmaceutical Assocs. For oral formulations, lonafarnib and/or ritonavir alone or with suitable excipients to make tablets, powders, granules or capsules, e.g. conventional excipients such as lactose, mannitol, cornstarch or potato starch; binders such as cellulose, cellulose derivatives, gum arabic, cornstarch or gelatin; disintegrants such as cornstarch, potato starch or sodium carboxymethylcellulose; lubricants such as talc or magnesium stearate; and, optionally, diluents, buffers. , wetting agents, preservatives and flavoring agents, in pharmaceutical formulations of the present invention comprising, consisting essentially of, or consisting of lonafarnib.

The term "pharmacologically acceptable salt" includes salts that retain the biological effectiveness and optionally other properties of the free salts, as well as inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, nitric , phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, malic acid, maleic acid, succinic acid, tartaric acid, and citric acid. Where embodiments of the disclosed agents form salts, these salts are within the scope of the present disclosure. References to any agent in the formulations herein are understood to include references to salts thereof, unless otherwise specified.

As used herein, the term "polymer" refers to an organic substance composed of multiple repeating structural units (monomeric units) covalently linked together. The term "copolymer" as used herein includes organic and inorganic polymers. In some embodiments, the polymer is a naturally occurring compound (e.g., a protein-based polymer such as collagen, albumin or gelatin, or a multi-polymer such as alginate, cyclodextrin, dextran, agarose, chitosan, hyaluronic acid, starch or cellulose). sugars). In some embodiments, the polymer is a semi-synthetic compound (eg, a cellulose derivative). In some embodiments, the polymer is a synthetic compound (eg, polyethylene glycol, poloxamer, polylactide, acrylic acid polymer, or polyamide). In some embodiments, the polymer is a natural biodegradable polymer such as albumin, collagen, gelatin, or starch. In some embodiments, the polymer is a synthetic biodegradable polymer (eg, polylactide, polyamide). In some embodiments, the polymer is a non-biodegradable polymer (eg, polyethylene, polymethylmethacrylate, polyvinylpyrrolidine, or cellulose derivatives).

"Proton pump inhibitors" are a class of antisecretory compounds that reduce gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of gastric parietal cells. Since this enzymatic system is viewed as an acid (proton) pump within the gastric mucosa, inhibitors of this system are characterized as gastric acid pump inhibitors in that they block the final step of acid production. This effect is dose-dependent and causes inhibition of basal and stimulated acid secretion regardless of stimulation.

The term "therapeutically effective amount," as used herein, refers to an administered agent that treats to some extent the disease, disorder or condition, e.g. compounds, inhibitors and/or drugs) and/or prevent to some extent one or more of the symptoms of a disease or infection that the subject being treated has developed or is at risk of developing refers to the amount to

The terms "treatment", "treating" and "treating" refer to the use of agents to reduce or ameliorate the pharmacological and/or physiological effects of a disease, disorder or condition and/or symptoms thereof. defined as using to address a disease, disorder or condition. "Treatment," as used herein, includes any treatment of a disease in a human subject, including (a) the disease in a subject determined to be susceptible to the disease but not yet diagnosed as infected with the disease; (b) interfere with the development of the disease; and/or (c) ameliorate the disease, i.e. cause regression of the disease and/or reduce one or more disease symptoms. to mitigate; "Treatment" is also meant to encompass delivery of inhibitors that provide pharmacological effects even in the absence of the disease or condition. For example, "treatment" includes delivery of disease or pathogen inhibitors that provide an enhanced or desired effect (eg, reduction of pathogenic viral load, reduction of disease symptoms, etc.) in a subject.

The term "undetectable" when used with respect to HDV RNA levels means that no HDV RNA copies are detected by the assay method used. In some embodiments, the assay is quantitative RT-PCR. The term "essentially undetectable" when used with respect to HDV RNA levels means that less than 50 HDV RNA copies/mL serum or plasma detectable by the assay method used (e.g., quantitative RT-PCR), and sometimes It means less than 25 HDV RNA copies/mL, sometimes less than 10 HDV RNA copies/mL.

The term "unacceptable gastrointestinal side effect" refers to gastrointestinal side effects that prevent the patient from completing the recommended course of treatment.

The term "dosage unit form" as used herein refers to a physically discrete unit suitable as a single dosage for human subjects, each unit containing a pharmacologically acceptable diluent One or more compounds (e.g., antiviral compounds and/or potentiators as described herein) calculated in amounts sufficient to produce the desired therapeutic effect in association with an agent, carrier, or vehicle contains a predetermined amount of

All deuterated analogues of any of the active pharmaceutical ingredients described herein, including but not limited to lonafarnib, and the potentiators ritonavir and cobicistat (compounds containing one or more deuterium atoms Another compound, which is a deuterated analogue of the "parent compound", is included by reference to the parent compound for the purposes of this invention when it differs from the parent compound only by the replacement of one or more hydrogen atoms of .

All stereoisomers, e.g., enantiomeric forms, of any of the agents described herein, including but not limited to lonafarnib, ritonavir, cobicistat and any other active pharmaceutical agents described herein. may exist in the absence of an asymmetric carbon) and diastereomeric forms that may exist due to the asymmetric carbon on the various substituents are contemplated within the scope of this disclosure. Individual stereoisomers of the compounds of the present disclosure may, e.g., be essentially free of other isomers, or e.g., as racemates or in all other or other selected stereoisomers. may be mixed with Stereogenic centers in the compounds of the disclosure may have the S or R configuration as defined by the IUPAC 1974 Recommendations.

II. INTRODUCTION In one aspect, the present invention relates to the treatment of patients infected with hepatitis D virus (HDV) by co-administering the prenyltransferase inhibitor lonafarnib and the CYP3A4 inhibitor ritonavir. As described below, 100 mg BID lonafarnib administration for 28 days has been found to reduce viral load, but this reduction was not sufficient to be developed as a therapy. Higher doses of lonafarnib were poorly tolerated and produced unacceptable levels of adverse events. Thus, when administered at 200 mg BID, serum levels of lonafarnib declined after approximately one month of treatment, generally attributed to poor tolerability, poor patient compliance, and loss of drug across the GI tract. it is conceivable that. Serum levels of lonafarnib were lower than expected when dosed at 300 mg BID, which may also be a result of poor tolerability. See, for example, Table 11 below. Thus, while administration of 100 mg BID lonafarnib was not sufficiently effective, higher doses were associated with significant GI-related adverse effects and were inappropriate treatments as routine treatment for HDV-infected patients. became.

The present invention provides, in part, that administration of lonafarnib in combination with ritonavir according to the dosing regimens described herein (“lonafarnib-ritonavir co-therapy”) is effective in treating HDV, compared to lonafarnib alone. It relates to the discovery that it produces excellent effects. Surprisingly, administration of 100 mg lonafarnib BID and 100 mg ritonavir QD produced higher serum concentrations of lonafarnib than those seen with lonafarnib monotherapy measured after 56 days of treatment, although adverse effects were less frequent. (see, eg, Tables 10 and 11 below). It has also been found that low-dose lonafarnib (e.g., 25 mg lonafarnib BID or 50 mg lonafarnib BID) administered in combination with ritonavir is effective in reducing HDV RNA viral load and is better tolerated. (see, eg, FIGS. 15A-B and Table 16 below).

Lonafarnib-ritonavir co-treatment may also be supplemented with prophylactic administration of GI-modifying agents (particularly prophylactic administration of one or more of antiemetics, antidiarrheals and antacids) to improve patient efficacy. We have found that it can be combined with Accordingly, one aspect of the present invention relates to lonafarnib-ritonavir co-treatment in combination with prophylactic administration of a combination of GI modifying drugs.

In one embodiment, the patient undergoing lonafarnib-ritonavir co-treatment is administered a daily dose of lonafarnib of 50-150 mg/day, such as 50 mg/day, 75 mg/day, 100 mg/day or 150 mg/day, A daily dose of 100 mg to 200 mg/day, such as 100 mg/day or 200 mg/day of ritonavir is administered. The above constant doses can be achieved by QD or BID administration of lonafarnib and QD or BID administration of ritonavir. Preferably, each dose of lonafarnib is 75 mg or less, such as 50 mg or less, and each dose of ritonavir is 100 mg or less. In one approach, lonafarnib is administered BID and ritonavir is administered QD. In one approach, both lonafarnib and ritonavir are administered BID. In one approach, both lonafarnib and ritonavir are administered QD.

III. HDV Treatment In one aspect, the present invention provides for treating HDV infection, wherein an HDV-infected patient is treated by oral administration of lonafarnib and ritonavir (which may also be referred to as "lonafarnib administration,""lonafarnib-ritonavirco-therapy," etc.). provide a method of In some embodiments, lonafarnib and ritonavir are administered according to the doses and dosing schedules described herein. In some embodiments, HDV-infected patients receive prophylactic treatment with one, two, or three or more classes of gastrointestinal (GI) modifying drugs. In some embodiments, patients receiving lonafarnib-ritonavir co-treatment are also treated with an interferon (eg, non-pegylated or pegylated interferon-alpha or interferon-lambda).

Lonafarnib has been studied for the treatment of solid and hematologic malignancies, Hutchinson-Guilford progeria syndrome and chronic hepatitis delta virus infection, but is not approved for any indication. The majority of reports of lonafarnib administration involve administering lonafarnib to cancer patients in combination with one or more antineoplastic agents.

Ritonavir (CAS registry number 155213-67-5) is available from AbbVie, Inc.; is marketed under the trade name Norvir.RTM., and is administered as an antiretroviral agent in combination with other antiviral agents for the treatment of HIV-1 infected individuals. Miller et al. , 2015, Infection and Drug Resistance, 8:19-29. The recommended dose of ritonavir for treatment of HIV-1 in adult patients is 600 mg orally twice daily with meals. See Norvir® package insert. Ritonavir is also used as a pharmacological enhancer or enhancer. Pharmacokinetic "boosting" refers to pharmacological enhancement of orally administered drugs by co-administration with pharmacological enhancers that make these drugs more effective. Ritonavir is used to enhance the Cmax of proteases used to treat HIV infection. Ritonavir's potentiating effect is caused by several properties of the drug. Ritonavir inhibits two key steps in metabolism.

First, ritonavir inhibits first-pass metabolism upon absorption. Enterocytes that line the intestinal tract contain CYP3A4, one of the key cytochrome P450 isoenzymes involved in drug metabolism, and P-, an efflux transporter that can effectively pump drugs out of the intestinal wall and back into the intestinal lumen. Contains both glycoproteins. Ritonavir inhibits both of these proteins. Thus, co-administration of ritonavir with drugs that are transported by P-glycoprotein and/or metabolized by enterocyte CYP3A4 may increase the Cmax of the co-administered drug. Second, ritonavir inhibits CYP3A4 in the liver, thereby preserving the plasma half-life of the drug.

Several factors make it impossible and difficult to predict what an acceptable dose of ritonavir will be for use as a potentiator.

First, the potentiation effect of ritonavir varies widely and unpredictably depending on the first (ie, co-administered) drug. This showed that the effect of co-administration of ritonavir with the primary drug ranged from a 350-fold increase in the AUC of the primary drug (fluticasone propionate, delivered as a water-soluble nasal spray) to an 11-fold increase (sidenafil), As indicated by the Norvir® package insert (available on the FDA website www.rxabbvie.com/pdf/norvirtab_pi.pdf) showing up to a 1.2-fold increase (trimethoprim). Even within a single drug class there are large variations. For example, in a meta-study of 17 dose-ranging pharmacokinetic studies of protease inhibitors, Hill et al. evaluated the ritonavir-enhancing effects of seven protease inhibitors: amprenavir, atazanavir, darunavir, indinavir, lopinavir, saquinavir and tipranavir at doses of 50-800 mg daily. Hill concluded that ritonavir had a dose-dependent enhancing effect on indinavir, tipranavir and lopinavir, but that the enhancing effect of ritonavir on darunavir or saquinavir did not correlate with dose.

Also, the pharmacokinetics of ritonavir in patients with hepatitis are likely to be more unpredictable compared to other treatment populations. Li et al. reported that hepatic CYP3A4 expression is decreased in individuals with chronic HBV infection. Although the subpopulation of HBV-infected patients co-infected with HDV was not tested separately, it is likely that CYP3A4 reduction occurs in HDV-positive individuals. Li et al. , 2006, Zhonghua Yi Xue Za Zhi, 86:2703-2706.

It has also been reported that ritonavir can inhibit P-glycoprotein found in peripheral blood lymphocytes. Lucia et al. , 2001, J Acquir Immune Defic Syndr. 27:321-30. If lonafarnib is a substrate for P-glycoprotein, co-administration of ritonavir may allow less lonafarnib to be transported back out of the cell, thereby increasing the intracellular half-life of the drug.

In addition, the HDV patient subpopulation is characterized by higher levels of cirrhosis (occurring in approximately 60-70% of patients with chronic hepatitis D) than those infected with HBV alone. The pharmacokinetics of ritonavir in HDV patient populations are less predictable compared to other populations with lower levels of cirrhosis or no cirrhosis.

Therapeutic efficacy of co-administration of lonafarnib and ritonavir to patients with chronic HDV was not known prior to the present invention, and the medical literature prior to the present invention does not state that it is safe to treat patients with HDV and patients with chronic HDV infection. Tolerable and effective dosing regimens (eg doses and dosing schedules) were not described.

Also, the side effect profile of administration of lonafarnib and co-administration of lonafarnib and ritonavir has not been previously determined. Diarrhea, nausea and vomiting have been reported as side effects of both lonafarnib (see Schering IB) and ritonavir administration (see Norvir package insert). Administration of 200 mg BID lonafarnib was characterized as "well-tolerated" in cancer patients. Hanrahan et al. , 2009, "A phase II study of Lonafarnib (SCH66336) in patients with chemistry, advanced squamous cell carcinoma of the head and neck," Am J Clin Oncol. 32:274-279 (describing lonafarnib treatment after platinum-based therapy for recurrent SCCHN) and List et al. , 2002, Blood, 100:789A (200 mg BID of lonafarnib was well tolerated in patients with advanced hematopoietic malignancies). However, the side effect profile of administration of therapeutically effective levels of lonafarnib to patients with chronic HDV infection was unknown, and the side effect profile of lonafarnib-ritonavir co-treatment was unknown for either population.

Effect of Lonafarnib Administration on HDV Infection As described in Example 1 below, a cohort of patients with chronic hepatitis delta (HDV) received treatment with 100 mg lonafarnib BID for 28 days and compared It showed a mean change in HDV RNA levels from baseline to Nadia of -0.74 log HDV RNA copies/mL compared to -0.24 log HDV RNA copies/mL. See also Table 1 below. Plasma levels of lonafarnib ranged from 200 ng/mL to 1,100 ng/mL during treatment, with subjects with higher plasma levels of lonafarnib experiencing a greater decrease in HDV RNA titers during treatment. See Figure 2. However, a stronger reduction in viral load was desired.

As described in Example 2 below, administration of higher doses of lonafarnib to HDV-infected patients resulted in a more dramatic reduction in viral load, but was unacceptably well tolerated. In patients receiving 200 mg BID lonafarnib for 28 days, the mean change in viral load was −1.63 log HDV RNA copies/mL. The mean change in viral load was −2.00 log HDV RNA copies/mL in patients receiving 300 mg BID lonafarnib for 28 days. See also Table 1 below.

Although daily administration of 200 mg or 300 mg BID lonafarnib produced superior viral load reduction in HDV patients compared to daily administration of 100 mg BID lonafarnib, administration of lonafarnib 200 mg BID or 300 mg BID produced significant side effects, which dosing regimen is not suitable for long-term treatment.

Effect of Lonafarnib-Co-Administration on HDV Infection As shown in Examples 4-6 and 12 below, lonafarnib-ritonavir co-treatment substantially reduced HDV viral load in patients at different dose combinations. Example 4 describes the superior efficacy observed with lonafarnib-ritonavir co-treatment compared to lonafarnib monotherapy. In patients receiving 100 mg BID lonafarnib in combination with 100 mg QD ritonavir for 28 days, the mean change in viral load was −2.2 log HDV RNA copies/mL. See also Table 1 below. Example 12 shows that for patients receiving 25 mg BID or 50 mg BID lonafarnib in combination with 100 mg BID ritonavir, the HDV RNA viral load was comparable to patients receiving higher doses of lonafarnib in lonafarnib-ritonavir co-treatment. Indicates that a decrease was observed. Moreover, in some instances, lonafarnib-ritonavir co-treatment reduced HDV viral load to undetectable levels at 8 weeks. See FIGS. 5 and 17. Therefore, according to the present invention, by using lower doses of lonafarnib alone or in combination with interferon with potentiators, patients can receive lonafarnib doses of 25 mg QD to 100 mg BID combined with 100 mg BID ritonavir and lower doses of 50 mg BID lonafarnib A significant therapeutic effect can be achieved at a preferred dose of

Thus, in various methods of the invention, each of lonafarnib and ritonavir is administered in combination with the other continuously, at least once daily (QD), in various embodiments twice daily (BID). , administered orally to HDV patients. In some embodiments, the lonafarnib-ritonavir co-treatment is administered daily for at least 30 consecutive days. In some embodiments, the lonafarnib-ritonavir co-treatment is administered daily for at least several months. In some embodiments, patients can receive lonafarnib-ritonavir co-treatment for the rest of their lives.

As shown in Figure 2, HDV viral load decreases with increasing plasma concentrations of lonafarnib. Correlation between lonafarnib serum levels and viral load in patients receiving lonafarnib-ritonavir co-treatment also showed Viral loads (see FIG. 7) were significantly higher in the former patients compared to those in patients who maintained serum lonafarnib concentrations in the range of about 1500-2500 ng/mL for about 21 days (see FIGS. 7 and 8). You will be found by doing good work. Referring also to Table 12, patients with the highest lonafarnib serum levels after 4 weeks of co-treatment had the greatest reduction in viral load, and patients with lonafarnib serum levels greater than 2,000 ng/mL generally had , showed a more dramatic reduction in viral load than patients with serum levels below 2,000 ng/mL (patient 4 being an exception to this trend).

Thus, in certain embodiments, lonafarnib and ritonavir are co-administered according to a schedule that produces serum lonafarnib levels greater than 2,000 ng/mL, such as greater than 4,000 ng/mL. In some embodiments, lonafarnib and ritonavir are from about 3,500 ng/mL to about 8,500 ng/mL (eg, from about 4,500 ng/mL to about 7,500 ng/mL, from about 5,000 ng/mL to about 6,000 ng/mL, about 5,500 ng/mL to about 6,500 ng/mL, about 6,000 ng/mL to about 7,000 ng/mL or 6,500 ng/mL to about 7,500 ng/mL) or about 5 ,000 ng/mL to about 7,000 ng/mL.

As used herein, serum lonafarnib levels or concentrations may be measured from serum samples obtained from the subject on a regular basis (such as weekly, biweekly, monthly or according to other schedules) and during the intervening period. can be estimated. For example, if a measurement of 4,000 ng/mL was obtained at 4 weeks and a measurement of 6,000 ng/mL was obtained at 6 weeks, then for the purposes of this analysis the intervening 2-week serum levels were It is concluded that it ranged from 4,000 to 6,000 ng/mL. In some embodiments, the first measurement is taken no earlier than one week after initiation of oral treatment.

Serum levels of lonafarnib can be measured using methods known in the art, including radioimmunoassays, chromatographic assays, mass spectroscopy, and the like. In some embodiments of the invention, patient serum samples were extracted using a protein precipitation method (acetonitrile). Samples were then loaded onto a Waters CSH C18, 2.1×50 mm, 1.7 μm column for separation followed by LC-MS/MS in positive ion mode for detection of lonafarnib. The assay range for lonafarnib was 1-2500 ng/mL.

Lonafarnib and Ritonavir Doses In some embodiments, the lonafarnib-ritonavir co-treatment includes lonafarnib in a total daily dose ranging from 50 mg to 150 mg (e.g., about 50 mg, about 75 mg, about 100 mg, about 125 mg, or about 150 mg total). and administering ritonavir in a total daily dose ranging from 100 mg to 200 mg (eg, a total daily dose of about 100 mg, about 150 mg, or about 200 mg). In some embodiments, the total daily dose of lonafarnib is 50 mg and the total daily dose of ritonavir is 200 mg. In some embodiments, the total daily dose of lonafarnib is 100 mg and the total daily dose of ritonavir is 200 mg. In some embodiments, the total daily dose of lonafarnib is 150 mg and the total daily dose of ritonavir is 200 mg.

In some embodiments, lonafarnib is administered BID. In some embodiments, lonafarnib is administered QD. In some embodiments, lonafarnib is administered at a dose of 25 mg BID. In some embodiments, lonafarnib is administered at a dose of 50 mg BID. In some embodiments, lonafarnib is administered at a dose of 50 mg QD. In some embodiments, lonafarnib is administered at a dose of 75 mg BID. In some embodiments, lonafarnib is administered at a dose of 75 mg QD. In some embodiments, lonafarnib is administered at a dose of 100 mg QD.

In some embodiments, ritonavir is administered BID. In some embodiments, ritonavir is administered QD. In some embodiments, ritonavir is administered at a dose of 100 mg BID. In some embodiments, ritonavir is administered at a dose of 100 mg QD. In some embodiments, ritonavir is administered at a dose of 75 mg BID. In some embodiments, ritonavir is administered at a dose of 50 mg BID.

Exemplary doses are provided in Table 2 by way of illustration and not limitation. Typically, lonafarnib and ritonavir are administered together (eg, self-administered by the patient) at approximately the same time (eg, at the same time or within about 15 minutes of each).

Each of embodiments 1-8 in Table 2 may be administered with a prophylactic GI modifying agent (eg, antiemetic, antidiarrheal, and antacid) and/or an interferon (eg, interferon alpha or interferon lambda). See Section V and Section VI below.

In some embodiments, lonafarnib and ritonavir (or similar potentiators such as cobicistat) are administered to the patient, and both the ritonavir and lonafarnib doses are administered for at least 30 days, usually at least about 60 days, or from 6 months to 1 month. At least 50 mg QD or at least 100 mg QD for 90 days or more, including 1 year or more. In some embodiments, administration is discontinued after viral levels have fallen to undetectable levels for a period of time (such as 1-3 months or longer). In one approach, suitable doses of lonafarnib/ritonavir include at least 30 days, more often at least 60 days, and typically at least 90 days or more. In one approach, treatment of hepatitis delta virus (HDV) infection in humans comprises a daily dose of about 50 mg/day, about 100 mg/day, or about 150 mg/day of lonafarnib (e.g., about 25 mg BID, 50 mg BID, 50 mg QD, 75 mg BID, 74 mg QD or 100 mg QD of lonafarnib) and a therapeutically effective amount of a CYP3A4 inhibitor (eg, ritonavir or cobicistat), thereby treating HDV infection. In one approach, ritonavir is administered at 100 mg QD.

In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in serum lonafarnib concentrations greater than 2,000 ng/mL when measured after 4 weeks of treatment. In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in serum lonafarnib concentrations greater than 3,000 ng/mL when measured after 4 weeks of treatment.

Patient Populations In some embodiments, patients treated with a co-therapy described herein are patients with chronic HDV infection. In some embodiments, the treated patient has a persistent chronic HDV infection of at least 6 months as documented by a positive HDV antibody (Ab) test and/or detectable HDV RNA by qRT-PCR. In some embodiments, a patient treated with a co-therapeutic method described herein has an acute HDV infection that is newly diagnosed or otherwise thought to have been absent in the patient for more than 6 months. is a patient with Diagnosis and pathogenesis of HDV are described, for example, in Wedemeyer et al. , Nat. Rev. Gastroenterol. Hepatol, 2010, 7:31-40. HDV is known to exist in various subtypes. The methods described herein are suitable for treating all HDV patients regardless of HDV subtype.

In some embodiments, the patient to be treated has at least 10 ⁴ HDV RNA copies per mL serum, e.g., at least 10 ⁵ HDV RNA copies per mL serum or plasma, at least 10 ⁶ HDV RNA copies per mL serum or plasma, 1 mL serum or has a viral load of at least 10 ⁷ HDV RNA copies per plasma, or at least 10 ⁸ HDV RNA copies per mL serum or plasma. In some embodiments, HDV viral load is measured using serum samples from patients. In some embodiments, HDV viral load is measured using a plasma sample from the patient. In some embodiments, viral load is measured by quantitative RT-PCR. qRT-PCR assays for quantification of HDV RNA in serum or plasma are known in the art, eg, as described above.

In some embodiments, the patient being treated exhibits one or more symptoms of liver dysfunction. In some embodiments, the patient exhibits one or more liver function parameters that are outside of normal parameters for healthy controls (eg, subjects not infected with HDV or HBV). In some embodiments, the liver function parameter is selected from the group consisting of serum albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and prothrombin activity. In some embodiments, the patient is at least 2-fold (e.g., at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, or or higher). Liver function parameters have been described in the art. For example, Limdi et al. , Postgrad Med J, 2003, 79:307-312. Methods for measuring these liver function parameters are known in the art and commercially available.

Dose Escalation and Dose Reduction In one embodiment, a patient being treated for HDV infection is treated with an escalating dosing regimen of lonafarnib, wherein one or more subsequent doses is a higher dose than one or more earlier doses. receive. In some embodiments, an ascending dosing regimen can increase patient tolerance to the drug and minimize side effects. In some embodiments, the dose escalation is administering lonafarnib at a first dose for a first treatment period, followed by lonafarnib at a second dose higher than the first dose for a second treatment period. including administering at In some embodiments, the duration of the first treatment period is the same as the duration of the second treatment period. In some embodiments, the first treatment period and the second treatment period are of different lengths. In some embodiments, dose escalation further comprises administering one or more additional doses of lonafarnib for one or more additional treatment periods.

In some embodiments, the duration of administration of each dose in an ascending regimen is no more than 1-4 weeks. The duration of each administration may be adjusted (eg, accelerated) by the clinician based on patient response. For example, without limitation, patients are administered lonafarnib 25 mg BID for the first two weeks, followed by 50 mg BID for the next two weeks, until a predetermined desired final dose is reached. Typically, escalating doses are co-administered with an appropriate dose, eg, 100 mg QD or BID of ritonavir. Dose escalation may continue up to 75 mg BID or greater (eg, 75 mg BID), including 100 mg BID or greater (eg, 100 mg BID).

In some embodiments, the lonafarnib-ritonavir co-therapy administers lonafarnib at a first dose during the first treatment period, and then if the patient does not experience unacceptable gastrointestinal side effects during the first treatment period. , administering a second dose of lonafarnib that is higher than the first dose during a second treatment period. By way of non-limiting example, in some embodiments, lonafarnib is administered at a first dose of 50 mg BID during the first treatment period and the patient experiences unacceptable gastrointestinal side effects during the first treatment period. If not, a second dose of 75 mg BID is administered during the second treatment period.

In some embodiments, lonafarnib-ritonavir co-therapy administers lonafarnib at a first dose during the first treatment period, and then if the patient experiences unacceptable gastrointestinal side effects during the first treatment period , administering a second dose of lonafarnib that is lower than the first dose during a second treatment period. By way of non-limiting example, in some embodiments, lonafarnib is administered at a first dose of 75 mg BID during the first treatment period and the patient experiences unacceptable gastrointestinal side effects during the first treatment period. If so, a second dose of 50 mg BID is administered during the second treatment period.

Treatment Duration, Induction of Immunological Reactivation, and Treatment Endpoints Patients may receive lonafarnib-ritonavir co-treatment for a defined duration, an unspecified duration, or until an endpoint is reached. Treatment may be continued daily continuously for at least 2-3 months. Treatment is typically for at least 30 days or 1 month, more often at least 60 days or 2 months, or at least 90 days or 3 months, even more often at least 120 days or 4 months. , sometimes for at least 150 days or 5 months, and sometimes for at least 180 days or 6 months. In some embodiments, treatment is continued for at least 6 months to 1 year. In other embodiments, treatment is continued for the remainder of the patient's life or until administration is no longer effective in maintaining the virus at sufficiently low levels to provide significant therapeutic benefit.

According to the methods of the present invention, some HDV patients respond to co-treatment herein by clearing the virus to undetectable levels, often after experiencing a hepatitis flare , followed by HDV Treatment may be discontinued unless and until levels return to detectable levels. Other patients experience a decrease in viral load and improvement in symptoms, but do not clear the virus to undetectable levels, but remain on "long-term therapy" as long as it provides therapeutic benefit.

In some cases, in the first course of therapy, the patient is treated to a particular endpoint (eg, viral load less than 10 ² or 10 ³ , hepatitis flare, or viral clearance). When the patient has achieved the endpoint, the provider may choose to discontinue therapy, such as lonafarnib-ritonavir co-treatment. Alternatively, when the patient has achieved the endpoint, the provider can choose to continue treatment, eg, lonafarnib-ritonavir co-treatment. For convenience, post-endpoint therapy is sometimes referred to as the "second (or "additional") course of treatment." The first and second courses of treatment can (and typically do) involve administering the same dosing regimen (ie, the same dose and dosing frequency). The terminology is sometimes convenient, but for the avoidance of doubt a patient may receive a "single course of treatment" extending to the endpoint.

In some embodiments, the patient receiving lonafarnib-ritonavir co-treatment has a baseline viral load of at least 10 ⁴ HDV RNA copies/mL serum and treatment is administered to less than 10 ² HDV RNA copies/mL serum. produce a viral load. In some embodiments, the patient with a baseline viral load of at least 10 ⁴ HDV RNA copies per mL of serum undergoes a first course of treatment that produces a viral load of less than 10 ² HDV RNA copies per mL of serum, followed by Subjected to additional courses of treatment, the viral load remains below 10 ² HDV RNA copies per mL serum after the additional course of treatment. In some embodiments, treatment results in an HDV viral load below the level of detection.

In some embodiments, the patient receiving lonafarnib-ritonavir co-treatment has a baseline viral load of at least 10 ⁵ HDV RNA copies/mL serum and treatment is administered to less than 10 ³ HDV RNA copies/mL serum. produce a viral load. In some embodiments, the patient with a baseline viral load of at least 10 ⁵ HDV RNA copies per mL of serum undergoes a first course of treatment that produces a viral load of less than 10 ³ HDV RNA copies per mL of serum, followed by Subjected to additional courses of treatment, the viral load remains below 10 ³ HDV RNA copies per mL serum after the additional course of treatment. In some embodiments, the patient receiving lonafarnib-ritonavir co-treatment has a baseline viral load of at least 10 ⁵ HDV RNA copies per mL serum and treatment is administered to less than 10 ² HDV RNA copies per mL serum. produce a viral load. In some embodiments, treatment results in an HDV viral load below the level of detection.

In some embodiments, the patient receiving lonafarnib-ritonavir co-treatment has a baseline viral load of at least 10 ⁶ HDV RNA copies/mL serum and treatment is less than 10 ⁴ HDV RNA copies/mL serum; Resulting in a reduced viral load of less than 10 ³ HDV RNA copies, or less than 10 ² HDV RNA copies. In some embodiments, the patient receiving lonafarnib-ritonavir co-treatment has a baseline viral load of at least 10 ⁷ HDV RNA copies per mL serum and treatment is less than 10 ⁵ HDV RNA copies per mL serum; Resulting in a reduced viral load of less than 10 ⁴ HDV RNA copies, less than 10 ³ HDV RNA copies, or less than 10 ² HDV RNA copies. In some embodiments, treatment results in an HDV viral load below the level of detection.

In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in a reduction in HDV viral load of at least 1.5 log HDV RNA copies/mL serum in the patient when measured after 8 weeks of therapy. In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in a reduction in HDV viral load of at least 2.0 log HDV RNA copies/mL serum in the patient when measured after 8 weeks of therapy. In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in a reduction in HDV viral load of at least 2.5 log HDV RNA copies/mL serum in the patient when measured after 8 weeks of therapy.

In some embodiments, treatment with lonafarnib-ritonavir co-therapy is associated with at least -1 log , or at least −2 log, or at least −3 log, or at least −5 log, or at least −6 log reduction in HDV viral load.

In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in a sustained reduction in HDV RNA levels. For example, in some embodiments, treatment results in a decrease in HDV RNA levels in the patient's serum or plasma, and this decreased level persists for a period of time (e.g., 1 month, 2 months, 3 months, 6 months, 9 months, 1 year, or longer). In some embodiments, the reduced HDV RNA levels persist for a period of time (eg, 1 month, 3 months, 1 year or more) after the course of treatment has ended. In some embodiments, the reduced HDV RNA levels persist for a period of time (eg, 1 month, 3 months, 1 year or more) while the course of treatment is ongoing. In some embodiments, the course of treatment results in HDV RNA levels (eg, serum HDV RNA levels or plasma HDV RNA levels) of less than 1,000 copies/mL. In some embodiments, HDV RNA levels remain below 1,000 copies/mL for at least 1 month, at least 3 months, at least 1 year, or longer. In some embodiments, the course of treatment results in HDV RNA levels (eg, serum HDV RNA levels or plasma HDV RNA levels) of less than 100 copies/mL. In some embodiments, HDV RNA levels remain below 100 copies/mL for at least 1 month, at least 3 months, at least 1 year, or longer. The phrase "remains less than" the initial measurement (e.g., 100 copies/mL or 100 IU/mL) for one month (or another specified period of time) is defined as at least one month after the initial measurement (e.g., 100 copies/mL or 100 IU/mL) or another specified time period), it means that the viral load measurement taken is not higher than the initial value. In some embodiments, the patient does not receive lonafarnib or lonafarnib-ritonavir co-treatment for a specified period of time. In some embodiments, the patient does not receive any anti-HDV therapy for a specified period of time.

In some embodiments, treatment as described herein is administered until HDV RNA levels are less than 3 log HDV RNA copies/mL (less than 1,000 copies/mL), or sometimes until HDV RNA levels are less than 2 log HDV RNA copies/mL. <100 copies/mL) or below the level of detection for a period of time. In some cases, treatment may be continued for a period of time (such as 1-3 months or longer) after the viral load has fallen to an acceptable low level (eg, undetectable levels). In some embodiments, treatment is continued until the HDV viral load drops to undetectable levels.

In some cases, treatment is continued until a "hepatitis flare" or "ALT flare" is observed in the patient. A hepatitis flare (or acute exacerbation) is an acute elevation of serum alanine aminotransferase (ALT) greater than 5-fold the upper limit of normal of about 40 U/L observed in chronic hepatitis B virus (HBV) infection. . HBV flare in HBV patients results from an immune response to HBV and its downstream mechanisms that are HLA-I restricted and mediated by cytotoxic T lymphocytes (CTLs). Higher ALT levels reflect more robust immune clearance of HBV. See Liaw, 2003, "Hepatitis flares and hepatitis be antigen seroconversion: an implication in anti-hepatitis B virus therapy," J Gastroenterol Hepatol 18:246-52. Although hepatitis flare has not been previously reported in response to anti-HDV treatment, signs of flare were observed in response to lonafarnib-ritonavir co-treatment as described herein. For example, two patients who received orally administered lonafarnib 100 mg BID and ritonavir 50 mg BID for 12 weeks exhibited an ALT flare characterized by ALT levels 10-20 times higher than normal individuals. Some patients received lonafarnib 200 mg BID or 300 mg BID monotherapy and received lower doses of lonafarnib in lonafarnib-ritonavir co-therapy (e.g., 75 mg BID lonafarnib combined with 100 mg BID ritonavir and 50 mg BID lonafarnib combined with 100 mg BID ritonavir). ALT flare was also observed in a patient with See Example 15 below.

The observation of flare in HDV patients suggests that co-treatment with ritonavir and lonafarnib at the doses described herein may have an unprecedented beneficial therapeutic effect in clearing HDV from patients. Without being bound by a particular theory or mechanism, in at least a subset of HDV patients, treatment with lonafarnib or lonafarnib-ritonavir co-therapy results in reactivation of the immune system that was suppressed as a result of HDV viral infection. it is conceivable that. Concomitant HBV/HDV infection often results in suppression of HBV replication in human patients, and in at least some HDV patients, suppression of HDV infection using the methods described herein results in at least transient HBV Causes an increase in level. Without being bound by theory, it is also believed that HDV suppresses the patient's immune response in parallel with the suppression of HBV. Suppression of HDV by lonafarnib treatment suppresses HBV and suppression of HBV replication. Some patients who have experienced immune reactivation and have not received anti-HBV therapy (e.g., antiviral nucleotide or nucleoside analogues) typically have at least 3 log changes in HBV DNA levels within about 12 weeks of starting therapy. has been found to show a transient increase in See, for example, Table 15 below. According to the present invention, an increase in HBV can be used as a surrogate marker to monitor the extent of immune reactivation in response to treatment (eg, efficacy of anti-HDV treatment). The ALT flare observed in at least one subset of HDV patients in response to HDV treatment, eg, as described in Example 15 below, indicates a reactivated immune response. Without being bound by a particular mechanism, upon immunological reactivation, the immune system begins to clear in response to HDV infection, resulting in ALT release from targeted HDV-infected hepatocytes manifesting as an ALT flare. it is conceivable that. Moreover, in at least some patients, immunological reactivation may result in a reduction in HBV levels or clearance of HBV infection. As described in Example 15 below, patients from various lonafarnib-treated cohorts who exhibited ALT flare subsequently exhibited suppression or clearance of HDV infection and suppression of HBV DNA levels. Without wishing to be bound by theory, in patients undergoing immune reactivation, as evidenced by the presence of ALT flares, suppression of HBV is at least partially due to an immune-mediated response. It is believed that there is. Thus, although HBV is often suppressed by HDV prior to LNF treatment, after immunological reactivation results in suppression or clearance of HDV, the observed sustained or even more pronounced suppression of HBV is associated with HBV. Reflects newly improved immune-mediated responses.

As described in Example 15 below, patients undergoing immunological reactivation have been found to exhibit certain characteristics with respect to HDV RNA and HBV DNA levels. For example, patients who experience immunological reactivation show a reduction in HDV RNA levels (e.g., at least 1 log) within the first two weeks of treatment, after which the reduced HDV RNA levels indicate that HDV levels are lower than those of Nadia. Maintained (if not further reduced) for at least an additional 2 weeks before increasing by at least 50% or more. In some embodiments, patients experiencing immunological reactivation exhibit a transient increase of at least 3 logs in HBV viral load.

In some embodiments, the method of inducing immune reactivation in a patient comprises administering lonafarnib or lonafarnib-ritonavir cotherapy at a first dose in a first course of treatment, followed by administration of lonafarnib in a second course of treatment. or administering the lonafarnib-ritonavir co-treatment at a second dose, wherein the second dose is different than the first dose. In some embodiments, the second dose is a lower lonafarnib dose (“step down”). In some embodiments, the first course of treatment ranges from about 4-12 weeks, eg, about 8-12 weeks. In some embodiments, the second course of treatment is about 2-4 weeks. In some embodiments, the first course of treatment is about 8 weeks and the second course of treatment is about 4 weeks.

In some embodiments, the patient is HDV-RNA negative within about 12-24 weeks after the onset of ALT flare. In some embodiments, the patient has normalized ALT levels (ie, ALT levels within the upper limit of normal as defined in the art) within about 12-24 weeks after the onset of ALT flare. In some embodiments, following immune reactivation, the patient's HDV viral load is reduced by at least 3 logs compared to the patient's baseline level at the start of treatment. In some embodiments, following immune reactivation, the patient's HBV viral load is reduced by at least 2 logs compared to the patient's baseline level at the start of treatment. In some embodiments, the patient's HDV viral load and/or HBV viral load is reduced to undetectable levels.

In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in improved liver function in the patient. In some embodiments, the improved liver function is one or more liver function parameters selected from the group consisting of serum albumin, bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and prothrombin activity. (eg, 1, 2, 3, 4, or more parameters) improvement. In some embodiments, treatment reduces at least 10%, at least 20%, at least 30%, at least 30%, Resulting in an improvement of at least 40%, at least 50%, or more. In some embodiments, treatment is in healthy control subjects not infected with HDV or HBV of one or more liver function parameters selected from the group consisting of serum albumin, bilirubin, ALT, AST, and prothrombin activity. resulting in improvement up to the level of In some embodiments, treatment with lonafarnib-ritonavir co-therapy results in improved liver biopsies (eg, as assessed by histological staining, immunohistochemical staining and/or fibrosis grading).

In some embodiments, treatment with lonafarnib-ritonavir co-therapy delays the need for liver transplantation in the patient. In some embodiments, treatment delays the need for liver transplantation for at least 3 months, at least 6 months, at least 9 months, or at least 12 months. In some embodiments, treatment delays the need for liver transplantation indefinitely.

Induction of ALT Flare and Subsequent Suppression of HDV In one aspect, methods are provided for inducing ALT flare in patients infected with HDV. As described herein, in at least some patients with chronic HDV treated with lonafarnib therapy (e.g., lonafarnib monotherapy or co-treatment with lonafarnib and ritonavir), ALT flare is induced followed by A significant reduction in HDV RNA titers occurs (see, eg, Figures 26-30). In at least some patients within about 12-24 weeks after the onset of ALT flare, patients test negative for HDV RNA. In some patients, a period of HDV RNA negativity is followed by an increase in HDV RNA levels. Without intending to be bound by theory, it is believed that low levels of virus remain in the "viral reservoir" of patients who test negative for HDV RNA using certain assays. In some situations, persistent virus may spread (see, eg, FIG. 26) and may require additional antiviral treatment if not eliminated by the patient's immune response. This additional antiviral treatment is typically therapy with lonafarnib, optionally as co-therapy with ritonavir and/or interferon. In general, further treatment involves administering lonafarnib at a lower dose and/or for a shorter duration than the initial Flare pretreatment regimen, optionally as co-treatment with ritonavir and/or interferon.

By way of illustration and not limitation, Table 3 shows an exemplary treatment protocol.

As noted above, in addition to or as an alternative to monitoring ALT flare, HBV DNA levels can be used to assess efficacy of initial treatment. As an example, patients with chronic HDV and a fibrosis score of <F3 are administered 50 mg BID lonafarnib in combination with 100 mg BID ritonavir for a first treatment course of 8 weeks (weeks 1-8). Patients will then receive 50 mg QD lonafarnib in combination with 100 mg BID ritonavir for a second treatment course of 4 weeks (weeks 9-12). At week 12, the patient's HBV DNA levels are measured. In one approach, anti-HBV therapy (eg, with ETV or TNF) for 36 weeks (weeks 13-48) is initiated if the patient has a greater than 3-log increase in HBV DNA.

If the patient shows no evidence of immunological reactivation (e.g., <3 log increase in HBV DNA), the patient is treated with anti-HBV therapy (e.g., ETV (or TNF)) will receive a course of treatment for 36 weeks (weeks 13-48).

Reduction in Hepatitis B Virus (HBV) Viral Load chronic hepatitis B virus that causes a reduction in HBV viral load in a patient compared to and/or compared to a similarly infected patient not receiving effective treatment to reduce the patient's HDV viral load (HBV)-infected patients. See Example 15 below. In some embodiments, a method of reducing HBV viral load in a patient infected with HBV and HDV comprises administering lonafarnib treatment described herein and detecting at least a 1 log reduction in HBV viral load Including. In some embodiments, treatment results in at least a 2-log reduction in HBV viral load. In some embodiments, the patient has not been treated with an antiviral nucleotide or nucleoside analogue.

Without intending to be bound by any theory, it is believed that at least some patients experience a drop in HBV viral load while receiving treatment according to the invention, and although some patients fail to clear the virus, They will maintain the virus at lower levels and experience health benefits as a result, compared to not receiving treatment.

IV. Pharmaceutical compositions and unit dosage forms
In another aspect, the invention provides unit dosage forms and pharmaceutical compositions for providing lonafarnib and ritonavir co-treatment. In some embodiments, the unit dosage form of lonafarnib or pharmaceutical composition is amorphous lonafarnib. In other embodiments, lonafarnib is crystalline. In some embodiments, the unit dosage form of ritonavir or pharmaceutical composition is amorphous ritonavir. In other embodiments, ritonavir is crystalline. In some embodiments, co-administration of lonafarnib and ritonavir is combined with prophylactic administration of 1, 2 or 3 GI stabilizing agents, as described in Section VI below. In some embodiments, lonafarnib and ritonavir co-administration is combined with interferon co-treatment, as described in Section V below.

Generally, for convenience, lonafarnib and ritonavir are formulated for oral administration and administered orally. However, other routes are preferred in some embodiments, and the present invention is therefore directed to the treatment of HDV infection using one or more other routes, such as intravenous (IV) administration or subcutaneous (SQ) formulations. Methods and compositions for the administration of lonafarnib and/or ritonavir to humans for As another example, the methods of the present invention may be practiced using patch technology, particularly patch technology using microneedles, to administer drugs subcutaneously. Parenteral administration may avoid or at least reduce GI and other side effects. Other routes suitable for drug delivery can be used, including systemic and local administration routes.

However, in many embodiments, lonafarnib and/or ritonavir are orally administered in solid dosage forms (eg, capsules, caplets, tablets, etc.). In certain embodiments, lonafarnib and/or ritonavir are orally administered as a liquid-containing soft gel capsule. In some embodiments, lonafarnib and/or ritonavir are administered as a liquid dosage form (oral suspension, syrup or elixir). Liquid dosage forms for oral administration may be provided in which each unit dose, eg, teaspoon, tablespoon, milliliter, etc., contains a predetermined amount of a composition comprising lonafarnib and/or ritonavir. In some embodiments, lonafarnib and ritonavir are administered as a combination of two different dosage forms (eg, lonafarnib tablet and ritonavir solution).

Lonafarnib and ritonavir can be co-administered separately (as separate unit dosage forms) or combined in an oral unit dosage form containing both lonafarnib and ritonavir in the practice of the methods described herein. When administered as separate unit forms, typically the lonafarnib and ritonavir doses are administered at about the same time, e.g., at the same time or within about 3 minutes of each, or within about 10, 30 or 60 minutes of each, Administered (eg, self-administered). In some embodiments, ritonavir is administered before lonafarnib is administered.

Although lonafarnib has been manufactured as 50 mg and 75 mg capsules, the preparation of dosage forms with different amounts of lonafarnib and ritonavir active ingredients is provided by the present invention and within the capabilities of those skilled in the art in view of the present disclosure. is within the range of In one embodiment, the pharmaceutical formulations of the present invention are lonafarnib formulated for oral administration as a unit dosage form containing 25 mg, 50 mg, or 75 mg of lonafarnib, including forms in which 50-100 mg of ritonavir is also present. contains When salts or solvates are used, equivalent amounts are required to be used, as will be readily appreciated by those skilled in the art.

Although ritonavir is commercially available as 100 mg tablets, 100 mg soft gelatin capsules and 80 mg/mL oral solution, preparing different amounts of active ingredient and dosage forms is within the capabilities of those skilled in the art in view of the present disclosure. is. In various embodiments, unit dosage forms useful in the methods of the present invention contain 50 mg or 100 mg, or some amount between 50 mg and 100 mg of ritonavir. When a salt or solvate is used, equivalent amounts are used, as will be readily appreciated by those skilled in the art.

Pharmaceutical formulations and unit dosage forms suitable for oral administration are particularly useful in the treatment of chronic conditions and therapies in which patients self-administer drugs. However, as noted above, in some cases, including but not limited to acute infections and life-threatening conditions, particularly those requiring hospitalization, intravenous formulations are desirable and the present invention is directed to Such formulations are also provided. The present invention can be used in aqueous or non-aqueous solvents such as vegetable or other similar oils, synthetic fatty acid glycerides, esters of higher fatty acids or propylene glycol, and optionally solubilizers, tonicity agents, suspending agents. Lonafarnib and/or ritonavir can be formulated into an injectable preparation according to the invention by dissolving, suspending or emulsifying the active pharmaceutical substance with conventional additives such as emulsifiers, stabilizers and preservatives, A pharmaceutical formulation is provided. A unit dosage form for injection or intravenous administration can be included in the composition as a solution in sterile water, saline, or another pharmaceutically acceptable carrier. Suitable amounts of active pharmaceutical ingredient for unit dosage forms of lonafarnib and/or ritonavir are provided herein.

Lonafarnib-Ritonavir Co-Formulations In some embodiments of the invention, lonafarnib and ritonavir are delivered to the patient (ie, "co-formulated") in the same unit dosage form. For example, a dosage form may contain lonafarnib and ritonavir (along with excipients and adjuvants). Without limitation, lonafarnib and ritonavir may be provided as a mixture, a multiparticulate formulation (which may contain small particles of lonafarnib in a matrix comprising ritonavir), a bilayer formulation, a tablet-in-a-tablet formulation, and the like. Such forms for co-administration include other drugs (see, e.g., US Patent Application Publication No. 2009/0142393 and US Patent Application Publication No. 2008/0021078, and International Patent Publication No. WO2009/042960). , each incorporated herein by reference), and such methodologies can be used in accordance with the present disclosure to prepare suitable unit dosage forms . Liquid formulations comprising lonafarnib and ritonavir provided herein can also be used for co-administration.

In some embodiments, lonafarnib and ritonavir are formulated with a copolymer. In some embodiments, the copolymer is from povidone (polyvinylpyrrolidone), hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC), hypromellose phthalate, polyvinylpyrrolidone-vinyl acetate copolymer, hypromellose-acetate-succinate, and mixtures thereof. selected from the group consisting of In some embodiments, the copolymer is any one of povidone, hydroxypropylcellulose, HPMC, hypromellose phthalate, polyvinylpyrrolidone-vinyl acetate copolymer, or hypromellose-acetate-succinate. In some embodiments, the copolymer is a mixture of two or more of povidone, hydroxypropylcellulose, HPMC, hypromellose phthalate, polyvinylpyrrolidone-vinyl acetate copolymer and hypromellose-acetate-succinate. In some embodiments, the copolymer is povidone, hydroxypropylcellulose, or hydroxypropylmethylcellulose (HPMC). In some embodiments, the copolymer is polyvinylpyrrolidone-vinyl acetate copolymer. In some embodiments, the copolymer is not povidone.

In some embodiments, the copolymer is povidone (also known as polyvinylpyrrolidone or PVP). In some embodiments, the copolymer is polyvinylpyrrolidone K12 (Povidone K12), polyvinylpyrrolidone K17 (Povidone K17), polyvinylpyrrolidone K25 (Povidone K25), polyvinylpyrrolidone K30 (Povidone K30) or polyvinylpyrrolidone K90 (Povidone K90). be. In some embodiments, the polyvinylpyrrolidone is polyvinylpyrrolidone K30. In some embodiments, the copolymer is polyvinylpyrrolidone-vinyl acetate copolymer. In some embodiments, the polyvinylpyrrolidone-vinyl acetate copolymer is Kollidon® VA64 copovidone.

In some embodiments, a unit dosage form or pharmaceutical composition comprising lonafarnib and ritonavir comprises lonafarnib in an amount of about 20 mg to about 100 mg, such as about 25 mg to about 100 mg, or about 50 mg to about 100 mg, and about 50 mg Contains ritonavir in an amount of to about 100 mg. In some embodiments, lonafarnib is present in an amount of about 25 mg, about 50 mg, about 75 mg or about 100 mg and ritonavir is present in an amount of about 50 mg, about 75 mg or about 100 mg.

In some embodiments, the unit dosage form or pharmaceutical composition is formulated for oral administration and contains lonafarnib and ritonavir in a ratio of about 1:2 (w/w) or about 1:4 (w/w). including. In some embodiments, the unit dosage form or pharmaceutical composition comprises lonafarnib and ritonavir in a ratio of about 1:2 (w/w). In some embodiments, the unit dosage form or pharmaceutical composition comprises lonafarnib and ritonavir in a ratio of about 1:4 (w/w). In some embodiments, the unit dosage form or pharmaceutical composition comprises lonafarnib and ritonavir in a ratio of about 0.75:1 (w/w).

In some embodiments, the unit dosage form or pharmaceutical composition is about 1:1:2 (w/w), 1:2:3 (w/w), or 1:1:5 (w/w) containing lonafarnib, ritonavir and copolymer in a ratio of

In some embodiments, a unit dosage form or pharmaceutical composition comprising lonafarnib, ritonavir and a copolymer is prepared according to the methods described in International Application No. PCT/US2016/028651, which is incorporated herein by reference. In some embodiments, the unit dosage form or pharmaceutical composition comprises a solvent (e.g., an organic solvent such as dichloromethane, chloroform, isopropyl alcohol, methanol, ethanol, acetone, ethyl methyl ketone, methyl isobutyl ketone, DMSO, water, optionally filtering the spray solution to remove insolubles; and substantially removing solvent from the spray solution; prepared by a process comprising In some embodiments, the solvent is removed by distillation or total evaporation of the solvent, spray drying, vacuum drying, tray drying, freeze drying or freeze drying, agitated thin film drying, or combinations thereof.

Specific Release Formulations Lonafarnib and/or ritonavir dosage forms, including co-formulations containing lonafarnib and ritonavir, are formulated for predetermined dissolution profiles, including immediate and controlled release (e.g., slow or sustained release). can be For example, lonafarnib may be formulated for delayed release and ritonavir may be formulated for immediate release (administered as separate dosage forms or as combination dosage form(s)). regardless of whether.

In some embodiments, a unit dosage form or pharmaceutical composition comprising lonafarnib, ritonavir, or lonafarnib and ritonavir as a co-formulation is formulated as a controlled or delayed release formulation. Methods for making controlled- or slow-release formulations are known in the art. By way of illustration and not limitation, in some cases, lonafarnib and optionally ritonavir can be formulated with a release retardant. Lonafarnib in this formulation has zero or relatively low drug release during a lag phase after administration to a subject, and then achieves a rapid release (“burst”) of drug after the lag phase ends. good too. The lag period typically ranges from about 0.25 to 3 hours, more often from about 0.5 to 2 hours. Many methods are known in the art for providing delayed burst release, such as by diffusion, swelling, osmotic burst or erosion (eg, based on inherent dissolution of drug and incorporated excipients). See US Patent Application Publication No. 2011/0313009, which is incorporated herein by reference.

In some cases, by way of example and not limitation, the release retardant is designed to allow release of lonafarnib and/or ritonavir upon exposure to a given condition in the body. In one embodiment, the release retardant is an enteric release agent capable of releasing the drug upon exposure to specific aspects of the gastrointestinal tract. In certain embodiments, enteric-release agents are pH-sensitive and are affected by changes in pH encountered in the gastrointestinal tract (pH-sensitive release). Enteric materials typically remain insoluble at the pH of the stomach and then allow release of the active ingredient in the higher pH environment of the lower gastrointestinal tract (eg, often the duodenum, or sometimes the colon). . In another embodiment, enteric materials comprise enzymatically degradable polymers that are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly the colon. Optionally, the unit dosage form is formulated with a pH sensitive enteric material designed to produce release within about 0.25 to 2 hours at or above a particular pH. In various embodiments, the specific pH can be, for example, about 4.5, 5, 5.5, 6 or 6.5. In certain embodiments, the pH-sensitive material allows at least 80% release of drug within 1 hour when exposed to a pH of about 5.5 or higher. In another embodiment, the pH sensitive material allows at least 80% release of drug within 1 hour when exposed to a pH of about 6 or greater.

Materials used for enteric release formulations, eg, as coating agents, are known in the art and are described, eg, in US Patent Application Publication No. 2011/0313009. Combinations of different enteric materials may also be used. Multilayer coatings using different polymers can also be applied. In some instances, enteric materials produce a delay in drug release ranging from about 0.25 to about 3 hours, sometimes from about 0.5 to about 4 hours.

One skilled in the art can adjust the lag period before delayed burst release from enteric-coated multiparticulates by varying the coating weight and composition of the enteric layer. For example, if the time in the stomach is less than 4 hours and some protection (1-3 hours) is desired after the dosage form leaves the stomach, it provides up to 4 hours of protection between administration and drug release. Appropriate levels of coating can be prepared. To identify the correct coating weight, samples of multiparticulates will be pulled from the fluidized bed coater over a range of coating weights and tested by in vitro elution to identify the appropriate coating level. Based on these results the exact coating weight will be chosen. Examples of enteric coated multiparticulates can be found in US Pat. No. 6,627,223.

Lonafarnib and/or ritonavir may be mixed (e.g., in a blend, intermix or continuous phase) and/or contained therein (e.g., its enclosed in or coated with). For example, the delayed burst release formulation can be in the form of one or more capsules containing lonafarnib and/or ritonavir. In other examples, lonafarnib and/or ritonavir may be in multiparticulate form, such as granules, microparticles (beads) or nanoparticles, coated with a release retardant.

As described below in Section VI, in one approach, it is contemplated that patients receiving lonafarnib will receive prophylactic administration of one or a combination of GI modifying agents. In one approach, one or more GI modifying agents are provided as a co-formulation with lonafarnib and/or ritonavir. For example, without limitation, lonafarnib, ritonavir and GI modifying drugs may be formulated as tri-layer tablets. In another approach, one or more GI modifying agents are provided in a generic pharmaceutical package (“co-package”), as described in Section VII below. In one approach, one or more GI modifying drugs are provided as an immediate release formulation and lonafarnib (and optionally ritonavir) are provided as a controlled release formulation. As long as at least one GI modifying drug is formulated for immediate release and lonafarnib is formulated for controlled release (e.g. slow release), formulated drugs with different release may be The combination may be co-packaged and/or co-formulated. In a preferred embodiment, the formulation allows the patient to administer lonafarnib and at least one GI modifying drug substantially simultaneously (e.g., simultaneously or within about 5 minutes of each). Using this approach, a patient may receive the pre-release benefit of a GI modifying drug without increasing the number of times per day that the patient must self-administer the therapeutic agent.

V. Interferon Co-Treatment In some embodiments, lonafarnib is used in combination with interferon to treat HDV infection (ie, HBV and HDV co-infection) or to reduce HDV viral load. In some embodiments, lonafarnib-ritonavir co-therapy is used in combination with interferon to treat HDV infection or to reduce HDV viral load.

Based on the type of receptors through which they signal, human interferons are classified into three major types. In various embodiments, any of type I-III interferons are used in combination with lonafarnib to treat HDV infection. All type I IFNs bind to a specific cell surface receptor complex known as the IFN-alpha receptor (IFNAR), which consists of IFNAR1 and IFNAR2 chains. The type I interferons present in humans are IFN-alpha, IFN-beta, IFN-epsilon and IFN-omega. Type II IFNs bind to the IFN-gamma receptor (IFNGR), which consists of the IFNGR1 and IFNGR2 chains. The type II interferon in humans is IFN-gamma. The recently classified group of type III interferons consists of three IFN-lambda molecules, termed IFN-lambda1, IFN-lambda2 and IFN-lambda3 (also called IL29, IL28A and IL28B, respectively). These IFNs signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12). Interferons suitable for use in the treatment methods described herein are described below.

In one embodiment, lonafarnib is administered in combination with other agents (such as interferon alpha or interferon lambda, and optionally ritonavir) at a lonafarnib dose of 100 mg QD or less. In one embodiment, the present invention treats HDV infection by administering at least 50 mg/day of lonafarnib (e.g., 25 mg BID, 50 mg BID, 75 mg BID, 100 mg BID, 50 mg QD, 75 mg QD, or 100 mg QD of lonafarnib) in combination with ritonavir and/or interferon. Provide a method of treatment. In one embodiment, the invention provides methods for treating HDV infection by administration of at least 100 mg lonafarnib QD or BID in combination with interferon and/or ritonavir.

In one approach, patients receiving lonafarnib (alone or in combination with a booster such as ritonavir) are also treated with an interferon (eg, interferon alpha or interferon lambda). In some embodiments, both lonafarnib and an interferon (e.g., interferon alpha or interferon lambda) are administered to the patient, and the lonafarnib dose is at least about 50 mg BID or QD, at least about 75 mg BID or QD, or about 100 mg BID or QD. In some embodiments, administration of lonafarnib and an interferon (eg, interferon alpha or interferon lambda) is concomitant. In some embodiments, administration of lonafarnib and an interferon (eg, interferon alpha or interferon lambda) is sequential. In some embodiments, the interferon is interferon alpha. In some embodiments, the interferon alpha is pegylated interferon alpha (eg, pegylated interferon alpha-2a, also referred to herein as "Pegasys"). In some embodiments, the interferon is interferon lambda. In some embodiments, the interferon lambda is pegylated interferon lambda (eg, pegylated interferon lambda-1a). It is therefore contemplated that HDV-infected patients receiving lonafarnib-ritonavir co-therapy may also be treated with interferon.

Administration of lonafarnib in combination with other agents such as interferons (eg, interferon alpha or interferon lambda) and ritonavir (Norvir) provides effective treatment at lower doses and/or reduced dosing frequency. In some cases, patients are administered lonafarnib, ritonavir and an interferon (eg, interferon alpha or interferon lambda). In some embodiments, the interferon is administered weekly at a dose of 120 micrograms (mcg) per week or 180 mcg per week.

In some embodiments, interferon-alpha (eg, Pegasys®, Genentech) is administered weekly. In some embodiments, interferon-alpha is administered at a dose of 120 mcg QW or 180 mcg QW. In some embodiments, pegylated interferon (Pegasys®) is administered at a dose of 180 μg per week.

In some embodiments, interferon lambda (eg, pegylated lambda, eg, pegylated lambda-1a) is administered weekly. In some embodiments, interferon lambda is administered at a dose of 120 mcg QW or 180 mcg QW. In some embodiments, interferon lambda is administered at a dose of 120 μg per week.

In these embodiments, administration of lonafarnib (eg, alone or in combination with ritonavir) and interferon is continued for at least 30 days, usually at least about 60 days, or even 90 days or more, including from 6 months to 1 year or more. . In one approach, administration is continued for about 30 days, more typically 30 or 60 days, and often for 6, 9 and 12 months. In some embodiments, administration is discontinued after viral levels have fallen to undetectable levels for a period of time (such as 1-3 months or more).

Interferons In one aspect, the invention provides combination therapy in which interferon-alpha or interferon-lambda is used in combination with lonafarnib. The terms "interferon-alpha" or "IFN-α" and "interferon-lambda" or "IFN-λ" as used herein refer to related polysaccharides that inhibit viral replication and cell proliferation and modulate immune responses. Refers to a family of peptides. Suitable interferons for the purposes of the present invention include pegylated IFN-α-2a, pegylated IFN-α-2b, consensus IFN, IFN-λ (eg IFN-λ1 such as IFN-λ1a), or pegylated Including, but not limited to, PEGylated IFN-λ (eg, PEGylated IFN-λ1 such as PEGylated IFN-λ1a).

Interferon-alpha The term "IFN-α" refers to natural IFN-α; synthetic IFN-α; derivatized IFN-α (eg, pegylated IFN-α, glycosylated IFN-α, etc.); and natural or synthetic IFN-α. Including analogues. The term "IFN-α" also encompasses consensus IFN-α. Thus, essentially any IFN-α or IFN-λ with antiviral properties as described for native IFN-α can be used in the combination therapy of the present invention.

The term "IFN-α" includes derivatives of IFN-α that have been derivatized (eg, chemically modified relative to the native peptide) to alter certain properties such as serum half-life. Thus, the term “IFN-α” includes polyethylene glycol-derivatized IFN-α (“pegylated IFN-α”), and the like. Pegylated IFN-α, and methods of making same, are described, for example, in US Pat. Nos. 5,382,657; 5,951,974; and 5,981,709. Pegylated IFN-α includes conjugates of PEG and any of the above IFN-α molecules, interferon alpha-2a (Roferon, Hoffman La-Roche, Nutley, NJ), interferon alpha-2b (Intron , Schering-Plough, Madison, NJ), interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon defined by determination of the consensus sequence of natural interferon alpha (Infergen®). Inc., InterMune, Inc., Brisbane, Calif.).

Accordingly, in some embodiments of the combination therapy of the invention, IFN-α is modified, ie pegylated, with one or more polyethylene glycol moieties. Two forms of pegylated interferon, pegylated interferon alpha-2a (40 kD) (Pegasys®, Genentech) and pegylated interferon alpha-2b (12 kD) (PegIntron®, Merck) are commercially available. , which differ in terms of pharmacokinetics, viral kinetics, tolerability profile, and thus dosing.

Peginterferon alpha-2a (Pegasys) consists of interferon alpha-2a (approximately 20 kD) covalently attached to a 40 kD branched polyethylene glycol (PEG). The PEG moiety is attached at a single site to the interferon alpha moiety through a stable amide bond to a lysine. Peginterferon alfa-2a has an approximate molecular weight of 60,000 Daltons. The biological activity of peginterferon-alpha-2a is derived from its interferon alpha-2a portion that influences both adaptive and innate immune responses to certain viruses. This alpha-interferon activates multiple intracellular signaling pathways that maximize the expression of interferon-stimulated genes that produce a range of antiviral effects, including blocking viral protein synthesis and inducing viral RNA mutagenesis. It binds to and activates the human type 1 interferon receptor on hepatocytes. Compared to native interferon alpha-2a, peginterferon alpha-2a has prolonged absorption and delayed clearing. Peginterferon alfa-2a is used as a fixed weekly dose. Peginterferon alfa-2a has a relatively constant absorption after injection, with a large distribution in the blood and organs.

Peginterferon alpha-2b (PegIntron) consists of interferon alpha-2b covalently attached to a 12 kD linear polyethylene glycol (PEG). The average molecular weight of this molecule is approximately 31,300 Daltons. Pegylated interferon alfa-2b is composed primarily of a monopegylated species (one PEG molecule attached to one interferon molecule) and a minor amount of a dipegylated species. Fourteen different PEG attachment sites on the interferon molecule have been identified. The biological activity of peginterferon alpha-2b is derived from the interferon alpha-2b portion that influences both adaptive and innate immune responses to certain viruses. This alpha-interferon activates multiple intracellular signaling pathways that maximize the expression of interferon-stimulated genes that produce a range of antiviral effects, including blocking viral protein synthesis and inducing viral RNA mutagenesis. It binds to and activates the human type 1 interferon receptor on hepatocytes. Compared to native interferon alpha-2b, pegylated interferon alpha-2b has sustained absorption, delayed clearance, and an extended half-life. Peginterferon alfa-2b is used as a weekly dose based on patient weight. Peginterferon alfa-2b has rapid absorption and broader distribution in the body.

The PEG molecule of the PEGylated IFN-α polypeptide is conjugated to one or more amino acid side chains of the IFN-α polypeptide. In certain embodiments, the pegylated IFN-α contains a PEG moiety at only one amino acid. In another embodiment, the pegylated IFN-α comprises PEG moieties at 2 or more amino acids, eg, IFN-α is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, It contains PEG moieties that bind 12, 13 or 14 different amino acid residues. IFN-α can be conjugated to PEG directly (ie, without a linking group) via an amino group, sulfhydryl group, hydroxyl group, or carboxyl group.

The term "IFN-α" also encompasses consensus IFN-α. Consensus IFN-α (also called “CIFN” and “IFN-con” and “consensus interferon”) is IFN-con1, IFN - amino acid sequences designated con2 and IFN-con3 and consensus interferons defined by determination of the consensus sequence of natural interferon alpha (e.g., Infergen®, Three Rivers Pharmaceuticals, Warrendale, PA), including but not limited to: is not limited to IFN-con1 is the consensus interferon agent in the Infergen® alfacon-1 formulation. The Infergen® consensus interferon formulation is referred to herein by its trade name (Infergen®) or by its generic name (interferon alfacon-1). DNA sequences encoding IFN-con can be synthesized as described in the above patents or other standard methods. In certain embodiments, the at least one additional therapeutic agent is CIFN.

Fusion polypeptides comprising IFN-α and a heterologous polypeptide are used in various embodiments of the combination therapy of the present invention. Suitable IFN-α fusion polypeptides include Albuferon-alfa ^™ (a fusion product of human albumin and IFN-α; Human Genome Sciences; see, eg, Osborn et al., 2002, J. Pharmacol. Exp. Therap. 303:540 -548), including but not limited to. Also suitable for use in the present methods are gene-shuffled forms of IFN-α. For example, Masci et al. , 2003, Curr. Oncol. Rep. 5:108-113. Other suitable interferons include Multiferon (Viragen), Medusa Interferon (Flamel Technology), Locteron (Octopus) and Omega Interferon (Intarcia/Boehringer Ingelheim).

In one embodiment of these combination treatments, pegylated interferon alfa-2a (Pegasys) is administered weekly at a dose of 180 micrograms (mcg) or 120 mg or 135 mcg (used for patients negatively responding to higher doses). Administer subcutaneously (SQ). In another embodiment of these combination treatments, pegylated interferon alfa-2b (PegIntron) is administered weekly SQ at a dose of 1.5 mcg/kg/wk. In other embodiments of these methods, alpha-interferon is used as follows: Consensus interferon (Infergen) administered SQ at 9 mcg to 15 mcg daily or 3 times per week; SQ at MIU to 9 MIU 3 times per week Interferon-alpha 2b (Intron A) recombinant SQ at 3 MIU-25 MIU three times per week; and Pegylated interferon lambda (IL- 28).

In some embodiments, the interferon is pegylated IFN-alpha 2a or pegylated IFN-alpha 2b. Suitable doses of lonafarnib/pegylated IFN-alpha 2a include, but are not limited to, 100 mg BID/180 mcg QW; 75 mg BID/180 mcg QW; 50 mg BID/180 mcg QW; or 25 mg BID/180 mcg QW. Suitable doses of lonafarnib/pegylated IFN-alpha 2b include 100 mg BID/1.5 mcg/kg patient weight QW; 75 mg BID/1.5 mcg/kg patient weight QW; 50 mg BID/1.5 mcg/kg patient weight QW; /1.5 mcg/kg patient weight QW.

Interferon Lambda The term “IFN-λ” encompasses IFN-lambda-1 (including IFN-lambda-1a), IFN-lambda-2 and IFN-lambda-3. These proteins are also known as interleukin-29 (IL-29), IL-28A and IL-28B respectively. Collectively, these three cytokines comprise the type III subset of IFNs. They are distinct from both type I and type II IFNs for a number of reasons, including the fact that they signal through heterodimeric receptor complexes that differ from the receptors used by type I or type II IFNs. be done. Although type I IFNs (IFN-alpha/beta) and type III IFNs (IFN-lambda) signal through distinct receptor complexes, they act on the same intracellular signaling pathways and It activates many of the same biological activities, including antiviral activity. Interferon lambda can be administered at any therapeutically suitable dose, including but not limited to 80, 120 or 180 mcg QW. In some embodiments, the dose for adults is 120 micrograms once weekly.

In some embodiments, interferon lambda (eg, interferon lambda-1 or interferon lambda-1a) is administered with lonafarnib and optionally ritonavir to treat an HDV infection in a patient. In some embodiments, interferon lambda is a pegylated form of interferon lambda (eg, pegylated interferon lambda-1 or pegylated interferon lambda-1a). In some embodiments, the interferon lambda is an interferon disclosed in US Pat. No. 7,157,559, incorporated herein by reference. In some embodiments, interferon lambda is administered at a dose of 120 μg per week. In some embodiments, interferon lambda is administered at a dose of 180 μg per week. In some embodiments, interferon lambda is administered subcutaneously. In some embodiments, the interferon lambda therapy is lonafarnib and optional Optionally administered with ritonavir. Example 15 describes a prophetic example of interferon lambda administration in combination with lonafarnib and optionally ritonavir.

In some embodiments, the interferon is pegylated IFN lambda-1a. Suitable doses of lonafarnib/pegylated IFN lambda-1a include 100 mg BID/180 mcg QW; 75 mg BID/180 mcg QW; 50 mg BID/180 mcg QW; 25 mg BID/180 mcg QW; but not limited to this.

Triple Drug Co-Therapies In some embodiments, an interferon lambda described herein is administered in combination with lonafarnib and ritonavir to treat an HDV infection in a patient. In some embodiments, the lonafarnib dose is 50 mg BID, the ritonavir dose is 100 mg BID, and the interferon lambda dose is 120 mcg QW. In some embodiments, the lonafarnib dose is 50 mg BID, the ritonavir dose is 100 mg BID, and the interferon lambda dose is 180 mcg QW. In some embodiments, the lonafarnib dose is 25 mg BID, the ritonavir dose is 100 mg BID, and the interferon lambda dose is 120 mcg QW. In some embodiments, the lonafarnib dose is 25 mg BID, the ritonavir dose is 100 mg BID, and the interferon lambda dose is 180 mcg QW. In some embodiments, the lonafarnib dose is 75 mg BID, the ritonavir dose is 100 mg BID, and the interferon lambda dose is 120 mcg QW. In some embodiments, the lonafarnib dose is 75 mg BID, the ritonavir dose is 100 mg BID, and the interferon lambda dose is 180 mcg QW. In some embodiments, the lonafarnib dose is 50 mg QD, the ritonavir dose is 100 mg QD, and the interferon lambda dose is 120 mcg QW. In some embodiments, the lonafarnib dose is 50 mg QD, the ritonavir dose is 100 mg QD, and the interferon lambda dose is 180 mcg QW. In some embodiments, the lonafarnib dose is 75 mg QD, the ritonavir dose is 100 mg QD, and the interferon lambda dose is 120 mcg QW. In some embodiments, the lonafarnib dose is 75 mg QD, the ritonavir dose is 100 mg QD, and the interferon lambda dose is 180 mcg QW. In some embodiments, the lonafarnib dose is 100 mg QD, the ritonavir dose is 100 mg QD, and the interferon lambda dose is 120 mcg QW. In some embodiments, the lonafarnib dose is 100 mg QD, the ritonavir dose is 100 mg QD, and the interferon lambda dose is 180 mcg QW.

VI. Prophylaxis with Gastrointestinal Modifying Therapies As described in Examples 2 and 4 below, some HDV-infected patients receiving lonafarnib monotherapy and lonafarnib-ritonavir co-treatment experienced gastrointestinal (GI) side effects. . GI side effects are not unexpected for compounds in the farnesyltransferase class. GI intolerance is also a known side effect of ritonavir when used as a protease inhibitor, even though ritonavir can be administered at doses as high as 1200 mg/day. However, the severity and persistence of these symptoms in lonafarnib-treated HDV patients who received relatively moderate doses of lonafarnib and ritonavir was unexpected. Drugs for the treatment of gastrointestinal irritation include antiemetics, antacids (H2-receptor antagonists and proton pump inhibitors) and antidiarrheals. Exemplary agents (for illustration and not limitation) are listed in Table 4 below.

According to the methods of the invention, lonafarnib is used in combination with at least one, at least two or at least three of an antiemetic, an antacid (H2-receptor antagonist or proton pump inhibitor) and/or an antidiarrheal. to allow continued compliance of patients on lonafarnib treatment. In one embodiment, an anti-diarrheal drug is administered. In one embodiment, an antidiarrheal and an antacid are administered. In one embodiment, anti-diarrheal and anti-emetic drugs are administered. In one embodiment, antidiarrheals, antacids and antiemetics are administered. In one embodiment, the antidiarrheal is lomotil (atropine/diphenoxylate) and/or the antacid is famotidine and/or the antiemetic is ondansetron.

In one approach, GI modifying therapy is administered on an as-needed (symptomatic) basis. In one approach, GI modifying therapy is administered prophylactically. As used herein in this context, "prophylactically" refers to administration to a patient in the absence or prior to the development of symptoms. Typically, prophylactic treatment requires dosing according to a fixed schedule (eg, daily) over the course of lonafarnib treatment.

In one approach, prophylactic treatment includes administration of ondansetron (antiemetic), lomotil (atropine/diphenoxylate) (antidiarrheal) and famotidine (antacid). For example, ondansetron 8 mg BID may be administered, lomotil (atropine/diphenoxylate) 5 mg QID or 5 mg BID may be administered, famotidine 20 mg BID may be administered.

In one approach, a GI modifying drug is administered daily prior to administration of lonafarnib. In one approach, a GI modifying drug is administered 30 minutes to 2 hours prior to administration of lonafarnib treatment.

In one approach, the GI-improving drug is administered daily at the same time that lonafarnib is administered, but lonafarnib (and optionally ritonavir) is administered in a delayed-release formulation so that the GI-improving drug begins to work before lonafarnib is released. including, for example, an enteric coating).

Prophylactic administration of GI modifying agents is generally continued during lonafarnib treatment.

In one approach, prophylactic administration of the GI modifying drug begins on day 1 of lonafarnib administration. In another approach, administration of one or more GI modifying agents begins prior to initiation of oral lonafarnib-ritonavir treatment. For example, in one embodiment, the patient is administered ondansetron the day prior to initiation of lonafarnib treatment. In one approach, one or more GI-modifying drugs are administered daily beginning two or more days prior to initiation of oral lonafarnib-ritonavir treatment.

In preferred embodiments, the GI modifying drug is administered according to a BID or QD schedule.

H2-Receptor Antagonists In one GI-modifying therapy embodiment, the GI-modifying therapy is an H2-receptor antagonist. In one embodiment of GI modifying therapy, ranitidine (Zantac®) is administered at doses up to 150 mg twice daily, up to 150 mg four times daily during lonafarnib treatment. In another embodiment of GI modifying therapy, famotidine (Pepcid®) is administered at doses of 40 mg once daily, up to 20 mg twice daily, up to 40 mg twice daily, during lonafarnib treatment. In another embodiment of GI modifying therapy, cimetidine (Tagamet®) is 400 mg once daily, up to 800 mg once daily, up to 1600 mg once daily, up to 800 mg twice daily, up to 300 mg four times daily , up to 400 mg QID, up to 600 mg QD, during lonafarnib treatment. In another embodiment of GI modifying therapy, nizatidine (Axid) is administered at doses of 150 mg once daily, up to 300 mg once daily, up to 150 mg twice daily, during lonafarnib treatment.

5-HT ₃ Antagonists In one embodiment of GI modifying therapy, the therapy is a 5-HT ₃ receptor antagonist. In one embodiment of GI modifying therapy, ondansetron (Zofran®) is administered up to 8 mg once daily, up to 8 mg twice daily, up to 8 mg three times daily 30 minutes to 2 hours before starting lonafarnib treatment administered at In this embodiment, administration is continued for at least the duration of lonafarnib treatment. In another embodiment of GI modifying therapy, granisetron (oral Kytril®) is administered at 2 mg or 1 mg twice daily given up to 1 hour prior to the start of lonafarnib treatment. In this embodiment, administration is continued for at least the duration of lonafarnib treatment.

NK-1 Receptor Antagonists In one GI-modifying therapy embodiment, the GI-modifying therapy is an NK-1 receptor antagonist. In one embodiment of GI modifying therapy, aprepitant (Emend®) is administered at a 125 mg dose on Day 1, followed by an 80 mg dose on Days 2 and 3 given 1 hour prior to the start of lonafarnib treatment. in combination with a 5-HT3 receptor antagonist and a corticosteroid as a 3-day treatment consisting of In another embodiment of these GI modifying treatments, a single 150 mg dose of fosaprepitant given up to 30 minutes prior to the start of lonafarnib treatment, followed by a single 12 mg dose of dexamethasone and a single dose of 5-HT3 receptor. A body antagonist (such as ondansetron), fosaprepitant up to a single 150 mg dose given up to 30 minutes before the start of lonafarnib treatment, followed by a single 8 mg dose of dexamethasone and a single dose of 5-HT3 receptor on day 1 Fosaprepitant (Emend® IV) is combined with a 5-HT3 receptor antagonist and a corticosteroid as a daily treatment consisting of a systemic antagonist (such as ondansetron), a single 8 mg dose of dexamethasone on days 2-4. It is administered in combination with a costeroid (dexamethasone).

Proton Pump Inhibitors In one embodiment of a GI modifying therapy, the GI modifying therapy is a proton pump inhibitor (PPI). In one embodiment of GI modifying therapy, omeprazole (Prilosec®) is administered in combination with an antacid at a dose of 20 mg once daily up to 40 mg once daily up to 4 days before the start of lonafarnib treatment. Administered for a period of time. In another embodiment of GI modifying therapy, omeprazole/sodium bicarbonate (Zegerid®) is administered at doses up to 20 mg once daily, 40 mg once daily at least 1 hour before meals and initiation of lonafarnib treatment administered during lonafarnib treatment. In another embodiment of GI modifying therapy, esomeprazole magnesium (Nexium®) is administered at 20 mg once daily, up to 40 mg once daily, 40 mg twice daily at least 1 hour before the start of lonafarnib treatment to be administered during lonafarnib treatment. In another embodiment of GI modifying therapy, esomeprazole strontium is administered at doses of 24.65 mg once daily, up to 49.3 mg once daily, up to 49.3 mg twice daily at least one hour prior to lonafarnib treatment. administered during lonafarnib treatment. In another embodiment of GI modifying therapy, lansoprazole (Prevacid®) is administered up to 2 hours prior to lonafarnib treatment for up to 14 days lansoprazole 15 mg once daily, up to 30 mg once daily, 60 mg daily Administered up to once, in doses of up to 30 mg twice daily, and up to 30 mg three times daily for the duration of lonafarnib treatment. In another embodiment of GI modifying therapy, dexlansoprazole (Dexilant®) is administered dexlansoprazole 30 mg once daily during lonafarnib treatment, up to 60 mg once daily up to 2 hours prior to lonafarnib treatment. administered to In another embodiment of GI modifying therapy, pantoprazole sodium (Protonix®) is administered at doses up to 40 mg once daily up to 7 days prior to lonafarnib treatment and up to 40 mg twice daily during lonafarnib treatment. be.

In some embodiments of the invention, GI-modifying therapies comprise proton pump inhibitors (PPIs) selected for their inhibitory effect on CYP3A4. PPI-mediated inhibition may help maintain therapeutically effective lonafarnib serum levels. Such inhibitory PPIs include, but are not limited to omeprazole and leprazole.

Antidiarrheal Drugs In one embodiment of GI modifying therapy, the treatment is an antidiarrheal drug. In one embodiment of GI modifying therapy, atropine/diphenoxylate (Lomotil®, Lonox®) is administered as two Lomotil tablets four times daily or Lomotil® liquid 10 ml four times daily ( 20 mg/day) is administered until initial control is achieved, after which the dose can be reduced to as little as 5 mg (2 tablets or 10 ml of liquid) daily. In another embodiment of GI modifying therapy, loperamide HCl (Imodium®) is 4 mg (2 capsules) followed by 2 mg (1 capsule) for each loose stool, 16 mg (capsule up to 8) doses. In another embodiment of GI modifying therapy, bismuth subsalicylate (Kaopectate®, Pepto-Bismol®) as 2 tablets or 30 mL every 30 minutes to 1 hour as needed, Up to 8 doses are administered in 24 hours.

VI. Kits and Packaging Lonafarnib, and/or ritonavir, and/or interferon and/or one or more GI-modifying drugs used to treat HDV patients can be supplied to physicians and patients, e.g., HDV patients, in pharmaceutical packaging or kits. can be delivered in Such packaging is intended to improve patient convenience and compliance with treatment regimens. Typically the packaging comprises paper (cardboard) or plastic. In some embodiments, the kit or pharmaceutical package further comprises instructions (eg, for administration according to the methods described herein).

In some embodiments, the pharmaceutical package or kit comprises 25, 50, 75, or 100 mg of lonafarnib per unit dose, or a unit dose form of lonafarnib comprising lonafarnib in an amount of 25 mg to 100 mg per unit dose, and 50 mg or 100 mg of ritonavir, or a unit dosage form containing ritonavir in an amount of 50 mg to 100 mg of ritonavir per unit dose. In some embodiments, the pharmaceutical package or kit comprises a unit dosage form of interferon, additionally or instead of ritonavir. In some embodiments, the pharmaceutical package or kit comprises an interferon unit dosage form comprising 120 mcg or 180 mcg interferon (eg, pegylated interferon lambda-1a) per unit dose. In some embodiments, the pharmaceutical package or kit comprises one or more GI modifying agents (e.g., one or more antiemetics, antacids (H2 receptor antagonists and proton pump inhibitors) or antidiarrheals) further comprising a unit dosage form of

In one embodiment, the kit or pharmaceutical package comprises lonafarnib and ritonavir at predetermined therapeutically effective doses, either in combination in a single unit dosage form or as separate unit doses. The dose (e.g., in mg) and unit dose form (e.g., tablet, capsule, immediate release, delayed release, etc.) of each drug may be any dose or form as described herein. (eg Section IV).

In one embodiment, the kit or pharmaceutical package contains doses suitable for multi-day administration, such as weekly, monthly or quarterly. In a preferred approach, for multi-day packaging, the dose (e.g., tablet) for each administration (e.g., once daily for QD administration, twice daily for BID administration, etc.) is administered on different days. or divided from the dose to be administered at different times.

In another embodiment, the package comprises a predetermined therapeutically effective dose of lonafarnib, ritonavir or a combination of lonafarnib and ritonavir, and one or more GI modifying agents combined in a single package, but within said package are separated into distinct compartments.

VIII. Other Antiviral Therapies HDV-infected patients receiving lonafarnib-ritonavir co-therapy are also treated with other antiviral agents such as nucleoside and nucleotide analogues, compounds used to treat HBV infection and other agents. It is contemplated that the

Nucleoside and Nucleotide Analogues Antiviral nucleoside or nucleotide analogues that may be used in combination with the lonafarnib-ritonavir co-therapy described herein include adefovir (Hepsera®), entecavir (Baraclude®), Lamivudine (Epivir-HBV®, Heptovir®, Heptodin®), telbivudine (Tyzeka®), tenofovir (Viread®) and ribavirin (Rebetol® or Copegus®) (registered trademark), etc.).

Compounds Used to Treat HBV In various combination therapies of the invention, lonafarnib is combined with an antiviral agent against HBV for the treatment of HDV. Currently approved anti-HBV drugs, with the exception of interferon, inhibit reverse transcriptase and are nucleoside or nucleotide analogues. These agents are effective against HBV but are ineffective against HDV because they do not clear the HBsAg that HDV needs to replicate. However, when used in the combination therapy of the present invention, improved patient efficacy may be achieved. Currently approved anti-HBV drugs include interferon alpha (Intron A®), pegylated interferon (Pegasys®), lamivudine (Epivir-HBV®, Zeffix® or Heptodin ®), adefovir pivoxil (Hepsera®), entecavir (Baraclude®), telbivudine (Tyzeka®, Sebivo®), clevudine (Korea/Asia), tenofovir (Viread (registered trademark)). Truvada®, a combination of tenofovir and emtricitabine, which has not yet been approved but has been shown to be effective in lowering HBV viral titers in early clinical trials, is the combination therapy of the present invention. is useful in

Other Therapeutic Compounds Other therapeutic compounds that may be administered with beneficial effects to HDV-infected patients being treated according to the present invention include nucleoside or nucleotide analogs; thiazolides; protease inhibitors; polymerase inhibitors; class C CpG toll-like receptor 7 and/or 9 antagonists; amphipathic helix disruptors or NS4B inhibitors; statins or other HMGCoA reductase inhibitors; immunomodulators; anti-inflammatory agents; cyclophilin inhibitors; and alpha-glucosidase inhibitors.

Other therapeutic modules Oral lonafarnib-ritonavir co-treatment may be one module in a therapeutic course for rapid and complete clearance of HDV infection. Accordingly, the treatment regimens described herein may be preceded or followed by complementary therapies.

As an example, some patients may benefit from an initial IV infusion of lonafarnib to rapidly achieve high blood levels of the drug. This level can be maintained by continuous or regular IV infusion for a period of time (one to several days or perhaps a week) before the patient is placed on the oral treatment more specifically described herein. In these embodiments, patients may be infused with drug to achieve therapeutic effects related to serum levels achieved with 50 mg BID administration (and higher doses). IV administration is recommended under the care of a physician or other trained health care professional (e.g., in a hospital setting) for prophylactic treatment, and to avoid or ameliorate AEs associated with oral administration at these high doses; Or with monitoring to interrupt IV administration if necessary. In other embodiments, subcutaneous injection to provide a depot form of the drug that maintains therapeutically effective blood levels of the drug for days or weeks is described herein for oral treatment. can be used to achieve similar therapeutically effective results.

IX. Use of Cobicistat as an Enhancer Although ritonavir is the most widely used CYP3A4 inhibitor, the present invention also provides combination treatments and therapies of lonafarnib with other CYP3A4 inhibitors. In one alternative, the present invention provides embodiments in which the pharmacokinetic enhancer cobicistat, also described elsewhere herein, is used in combination with lonafarnib instead of ritonavir.

Cobicistat (sold by Gilead Sciences under the trade name Tybost®) is a potent inhibitor of CYP3A. Like ritonavir, cobicistat "enhances" blood levels of other substrates of this enzyme, but unlike ritonavir, it has no antiviral activity. Also, although it has pronounced effects on the enzymatic system (CYP3A) involved in degrading certain drugs, it has many other potential adverse drug interactions that can contribute to a number of potentially harmful drug interactions. does not affect other enzymatic systems used by the drug.

In one aspect, the invention provides treatment of HDV patients using the methods and compositions described herein, except that an enhancing agent other than ritonavir is used. In one embodiment, the potentiator cobicistat is used in the methods and compositions described herein. Cobicistat is useful in combination therapies of the invention at its approved dose in combination with lonafarnib at any dose and dosing frequency described herein, or at any lower dose. In alternative embodiments, cobicistat is administered at lower (eg, 75 mg) and/or more frequent (eg, BID) doses than those approved for use in treating HIV infection. In some embodiments, lower doses of cobicistat are used (eg, 50 mg QD or 50 mg BID).

Exemplary doses for lonafarnib-cobicistat co-treatment are provided in Table 5 by way of illustration and not limitation. In some embodiments, lonafarnib is administered at 100 mg QD or 100 mg BID and cobicistat (Tybost®) is administered at 150 mg once daily.

Dosage schedules AG may each be administered with a prophylactic GI modifying agent (eg, antiemetics, antidiarrheals, and antacids) and/or an interferon (eg, interferon alpha or interferon lambda). See Section V and Section VI above. In one embodiment, the lonafarnib-cobicistat co-treatment is administered in combination with interferon.

X. EXAMPLES The following examples are offered to illustrate, but not to limit, the claimed invention.

Example 1. Treatment of HDV Patients with 100 mg Lonafarnib Administered BID This example demonstrates the efficacy of lonafarnib in reducing HDV RNA levels in patients with chronic HDV. Eight Group 1 patients (all with chronic HDV) were treated as follows: Six patients with chronic hepatitis delta (HDV) (Patients 1, 2, 4, 5, 6 and 8) Treated with lonafarnib, two patients (patients 3 and 7) received placebo for 28 days. Six patients in the active treatment group were dosed (orally) at 100 mg BID for 28 days. The mean change in HDV RNA levels from baseline to Nadia in the lonafarnib active treatment group was -0.74 log HDV RNA copies/mL and in the placebo group was -0.24 log HDV RNA copies/mL.

Patients 4, 5, 6 and 8 were responsive to treatment as defined by a reduction in quantitative serum HDV RNA levels from baseline to Nadia of 0.5 log HDV RNA copies/mL or greater during active treatment. there were. See Table 6 (showing changes in HDV RNA viral load for each patient during and after treatment) and Figure 1 (showing changes in log HDV RNA copies/mL levels for patients 4, 5 and 6 over time). The change in HDV RNA levels for Patient 4 from baseline to end of treatment (EOT) was -1.34 log HDV RNA copies/mL. The change in HDV RNA levels for Patient 5 from baseline to EOT was -0.82 log HDV RNA copies/mL. The change in HDV RNA levels for patient 6 from baseline to EOT was -1.41 log HDV RNA copies/mL.

HDV RNA viral load correlates with plasma concentration of lonafarnib.
Figure 2 shows the correlation between plasma levels of lonafarnib and viral load. Subjects with higher plasma levels of lonafarnib experienced greater decreases in HDV RNA titers during treatment. Plasma levels during treatment ranged from 200 ng/mL to 1,100 ng/mL.

Viral Rebound Post-Treatment Patients 4, 5 and 6 showed viral rebound or increased serum HDV RNA levels after discontinuation of lonafarnib treatment on day 28. After discontinuation of lonafarnib, Patient 4's HDV RNA levels increased by 1.7 log HDV RNA copies/mL. After discontinuation of lonafarnib, patient 5's HDV RNA level increased by 1.4 log HDV RNA copies/mL. Patient 6's HDV RNA level increased after discontinuation of lonafarnib. Patients 4, 5 and 6 showed a subsequent decline in HDV RNA levels beginning about 4-8 weeks after lonafarnib treatment was discontinued, suggesting a viral dynamic between HDV RNA and HBV DNA. It is thought to be caused by a virus.

Example 2. Treatment of HDV patients with 200 mg and 300 mg lonafarnib administered BID Having been infected with HDV as documented by a baseline HDV RNA viral titer ranging from 5.8 log HDV RNA copies/mL to 8.78 log HDV RNA copies/mL Six human subjects with known . were treated with either 200 mg BID or 300 mg BID doses of lonafarnib for 84 days.

Effect of 28 Days of Treatment At the end of 28 days of treatment, the mean change in viral load across 6 subjects from baseline to day 28 was −1.63 log copies/mL for the 200 mg BID group and 300 mg BID group. was −2.00 log copies/mL for See Table 7 and FIG.

Day 28 results showed superior efficacy of the 200 mg BID and 300 mg BID dosing schedules versus the 100 mg BID dosing schedule. However, additional efficacy with fewer side effects was thought to be required for significant therapeutic benefit.

Effects of Days 56-84 of Treatment When 200 mg BID and 300 mg BID administration was continued for 56 days (days 29-56 can be termed 2 months) and 84 days (days 57-84 can be termed 3 months), 6 The change in viral load across human patients plateaued or increased from 28-day viral load levels. This no change or increase in viral load was attributed to poor gastrointestinal tolerability to lonafarnib and associated poor compliance with the protocol. These 6 patients did not receive prophylactic GI modifying drugs to relieve gastrointestinal distress. Indications or drug absorption or both are considered suboptimal due to GI intolerance and associated side effects.

Example 3. Combination Treatment of HDV Patients with 100 mg BID Lonafarnib and Interferon Three human subjects known to be infected with HDV had baselines ranging from 4.34 log HDV RNA copies/mL to 5.15 log HDV RNA copies/mL at a dose of 100 mg BID in combination with 180 μg Pegasys (PEG interferon alfa-2a) per week for 56 days (2 months), as described by HDV RNA viral titers, and ALT values ranging from 155 to 174 IU/L. Treated.

At the end of 28 days, HDV RNA viral titers in all 3 patients declined from baseline with a range of -1.04 log HDV RNA copies/mL to -2.00 log HDV RNA copies/mL reduction in HDV-RNA, The average reduction in 3 subjects was −1.8 log HDV RNA copies/mL. At the end of 56 days, HDV RNA viral titers in all three patients continued to decline with a mean viral load reduction of 3 log copies/mL on day 56. ALT values in all 3 patients also declined from baseline through day 56, continued to decline after treatment was discontinued, and normalized in 2 of 3 patients by 4 weeks after treatment discontinuation. The upper normal limit for ALT values is estimated to be 40 U/L.

Changes in HDV RNA viral load and ALT values for each patient are shown in Table 8 below. See also FIG.

These viral load results show comparable efficacy to the 200 mg BID lonafarnib regimen and superior efficacy to the 100 mg BID lonafarnib regimen and fewer Grade 2 adverse events (AEs) compared to 200 mg BID lonafarnib .

Example 4. Combination Treatment of HDV Patients with 100 mg BID Lonafarnib and 100 mg QD Ritonavir at a dose of 100 mg BID of lonafarnib in combination with 100 mg QD of ritonavir for 8 weeks, substantially as otherwise described in Example 1, as described by line HDV RNA viral titers, and ALT values of 84-195 U/L. Treated.

At the end of week 4, HDV RNA viral titers in all three patients decreased from baseline ranging from -1.71 log HDV RNA copies/mL to at least -2.76 log HDV RNA copies/mL decrease in HDV-RNA. and the mean reduction across the three patients was -2.2 log HDV RNA copies/mL. At the end of week 8, all three patients' HDV RNA viral titers continued to decline, and patient 2 had undetectable viral titers. See FIG. The average viral load reduction for the three patients at eight weeks was -3.2 log HDV-RNA.

ALT values in all three subjects also decreased from baseline in the range of 35-50 U/L. The upper normal limit for ALT values is estimated to be 40 U/L. See Table 9, which also shows the change in HDV RNA viral load for each patient.

These results demonstrate superior efficacy compared to 200 mg BID and 300 mg BID lonafarnib monotherapy and to combination treatment of 100 mg BID lonafarnib and 180 μg Pegasys (PEG interferon alfa-2a) per week. Fewer grade 2 AEs were also observed compared to 200 mg BID lonafarnib. See Table 10.

Table 11 below shows lonafarnib monotherapy (200 mg BID or 300 mg BID), lonafarnib-ritonavir co-treatment (100 mg BID lonafarnib in combination with 100 mg QD ritonavir), and lonafarnib-ritonavir co-treatment (100 mg BID lonafarnib in combination with 180 mcg QW pegylated interferon) at specified time points. ) are the mean serum concentrations obtained in .

Example 5. Treatment of HDV Patients with Lonafarnib and Ritonavir
The examples show the anti-HDV effect of combination therapy of lonafarnib and ritonavir. Eight patients with chronic HDV infection will be treated with four different dose combinations of lonafarnib and ritonavir (orally administered) for 84 days under the regimen outlined in Table 12.

Results The changes in patient HDV RNA levels from baseline as a result of combination therapy with lonafarnib and ritonavir are summarized in Table 12 below.

Time courses showing changes in HDV RNA levels in patients 1-8 through days 28, 56 and 84 are shown in Figures 6A, 6B and 6C, respectively (changes compared to standardized baseline ). The mean change in log viral load was -1.89 after day 28, -1.86 after day 56, and -1.62 after day 84. Nadia was reached in 4-6 weeks, after which the viral load (VL) plateaued or, in some cases, slightly increased. Group 4 may have reached a saturable absorption point, potentially supporting greater efficacy of lower lonafarnib doses.

Groups 1 and 2 maintained the highest _Cmin . These two groups received either BID lonafarnib (group 1) or BID ritonavir (group 2). These results support the conclusion that higher or more frequent ritonavir doses, such as BID administration, are beneficial. FIG. 10 shows that QD administration of ritonavir (shown in the graph) provides lonafarnib (LNF) serum concentrations ranging from 2500-3500 ng/mL. Increasing ritonavir administration BID in patients can achieve higher lonafarnib serum concentrations >5000 ng/mL.

The correlation of decreased HDV RNA levels and increased serum levels of lonafarnib in hepatitis delta-infected patients treated with lonafarnib-ritonavir co-therapy is illustrated in patient 2 (Figure 7) and patient 8 (Figure 8). Patients with serum lonafarnib levels below 2000 ng/mL, e.g. A lower reduction (<1.5 log HDV-RNA) is possible.

Adverse Effects Table 13 summarizes patient adverse events during the first 6 weeks of treatment, with 75% (6 of 8 patients) of patients in the study receiving at least one dose during weeks 7-10. Indicates that reduction was required. Dose reduction often resulted in an increase or plateau in HDV RNA levels.

Lonafarnib doses were reduced in 6 of 8 patients (Patients 1, 2, 3, 4, 5, 8) due to side effects. Dose reductions correlated with viral load plateaus or increases. Lomotil and ondansetron were used in 3 of 8 patients (starting at week 4). Two of the three patients did not require dose reduction of lonafarnib.

Example 6. Treatment of HDV patients with low dose lonafarnib-ritonavir co-therapy and lonafarnib-ritonavir-pegylated interferon alfa triple co-therapy HDV values for 3 infected patients (patients 13, 14 and 15) are shown. At week 12, ritonavir was discontinued and PEG-IFN-α was administered (180 mcg QW). At week 16, ritonavir (100 mg BID) administration was resumed.

Results A time course showing changes in HDV RNA levels in patients 13, 14, and 15 is shown in Figure 12 (changes compared to normalized baseline). Viral loads at weeks 12 and 16 (lonafarnib-interferon co-treatment) were approximately constant (patients 13 and 15) or increased (patient 14). From weeks 16 to 20, the patient received triple co-treatment and produced a significant reduction in viral load (patients 13 and 14).

Example 7. Low Dose (50 mg BID) Lonafarnib Triple Drug Co-Treatment Three chronic HDV-infected patients (patients 25, 26 and 27) were treated with lonafarnib (50 mg BID), ritonavir (100 mg BID) and pegylated interferon alpha (180 mcg QW) for 4 weeks. See FIG. A significant reduction in viral load was seen at 2 weeks. At 4 weeks, all patients had significantly reduced viral loads relative to baseline. These results conclude that low-dose lonafarnib can be administered in combination with potentiators (e.g., ritonavir) and interferons (e.g., interferon-alpha or interferon-lambda) to enable patients to achieve significant therapeutic benefit. to support

Example 8. Triple Co-Treatment with Low (50 mg BID) and Very Low Dose (50 mg QD) Lonafarnib FIG. 14 shows the effect of triple co-therapy on viral load in three chronic HDV-infected patients. Patients 2 and 3 received 50 mg BID lonafarnib, 100 mg BID ritonavir and 180 mcg QW pegylated interferon alpha for 8 weeks. Patient 1 received 50 mg BID lonafarnib, 100 mg BID ritonavir, and 180 mcg QW pegylated interferon-alpha for approximately 3 weeks, at which time the lonafarnib dose was reduced to 50 mg QD (at week 8 when 50 mg BID was administered). 1 day). Patients received proton pump inhibitors (esomeprazole or rabeprazole on a QD basis) and antidiarrheals (lomotil or loperamide BID or TID).

As shown in Figure 14, after 8 weeks at the 50 mg BID dose, the mean reduction in log HDV viral load was greater than 2 (patient 3) or greater than 3 (patient 2), and at the 50 mg QD dose was greater than 3 (patient 1). The treatment was well tolerated, with diarrhea being the most prominent side effect, indicating that triple therapy is well suited for long-term treatment (>6 months).

Example 9: Exemplary Treatment Regimens This prophetic example describes treating HDV infection by administration of various doses of lonafarnib and ritonavir, as disclosed in Table 14 below. Patients infected with HDV self-administer the following regimen daily for 90-180 days: Patients' lonafarnib serum levels and HDV viral load are measured periodically during the course of treatment. After 90 days of treatment, the patient's viral load decreases above baseline.

Example 10. A phase 2 study evaluating the safety, tolerability, and pharmacodynamics of pegylated interferon lambda-1a (PEG-IFN-λ) monotherapy in patients with chronic hepatitis D virus infection. A phase 2 clinical trial protocol to evaluate the safety, tolerability, and pharmacodynamics of pegylated interferon lambda monotherapy in patients is described. The efficacy demonstrated by interferon lambda monotherapy in this protocol indicates that interferon lambda therapy in combination with lonafarnib, and optionally in combination with additional enhancing agents such as ritonavir, is effective in treating HDV infection. indicates

PEG-IFN-λ (2 dose levels of 120 μg per week or 180 μg per week) were administered by subcutaneous injection over a 48-week treatment period to increase HDV, ALT, and hepatitis B surface antigen (HBsAg) levels. The safety and tolerability of the treatment will be assessed on the basis.

At least 1 from the cohort of patients who received at least 80% of the total study drug dose over the entire 48-week treatment period and for whom Day 1 (baseline) and end-of-treatment (48 weeks) HDV viral load data are available Human patients show improvement in one or more of the endpoints described in the protocol at the study visit. In some embodiments, patients undergoing treatment with interferon lambda monotherapy exhibit a reduction in HDV viral load at the end of treatment compared to baseline. In some embodiments, patients undergoing treatment with interferon lambda monotherapy exhibit a reduction in HBV viral load at the end of treatment compared to baseline. In some embodiments, patients undergoing treatment with interferon lambda monotherapy exhibit decreased HBsAg levels at the end of treatment compared to baseline. In some embodiments, patients undergoing treatment with interferon lambda monotherapy exhibit improved clearance of HBsAg antigen.

Example 11. Triple Drug Co-Therapy This prophetic example describes treating HDV infection by administration of interferon lambda in combination with lonafarnib and ritonavir. Administration of pegylated interferon lambda in combination with lonafarnib and ritonavir provides effective treatment at lower doses and/or reduced dosing frequency.

Patients infected with HDV are administered pegylated interferon lambda at 120 mcg QW or 180 mcg QW in combination with one of the following lonafarnib + ritonavir dose combinations.
Lonafarnib 50 mg BID + Ritonavir 100 mg BID
Lonafarnib 25 mg BID + Ritonavir 100 mg BID
Lonafarnib 75 mg BID + Ritonavir 100 mg BID
Lonafarnib 50 mg QD + Ritonavir 100 mg QD
Lonafarnib 75 mg QD + Ritonavir 100 mg QD
Lonafarnib 100 mg QD + Ritonavir 100 mg QD
Lonafarnib 50 mg QD + Ritonavir 100 mg BID
Lonafarnib 75 mg QD + Ritonavir 100 mg BID
Lonafarnib 100 mg QD + Ritonavir 100 mg BID

During the course of treatment, the patient's HDV viral load is measured periodically. After 90 days of treatment, the patient's viral load decreases above baseline.

Example 12. Lonafarnib-ritonavir co-treatment combination regimens This example demonstrates the efficacy and tolerability of various combination regimens of lonafarnib and ritonavir, with or without pegylated interferon-α, in patients known to be infected with HDV. show tolerability. Thirty-eight patients were dosed as shown in Table 15 below. Treatment duration was 12-24 weeks. 72-hour pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed on days 1 and 28 of treatment. In addition, biochemical parameters and HDV RNA levels (measured by quantitative real-time PCR) were measured on days 1, 2, 3, 7, 14 and 28 and then every 4 weeks thereafter during treatment. .

For all treatment groups, HDV RNA viral load was measured after 4 and 8 weeks of treatment and compared to baseline HDV RNA viral load. As shown in FIG. 15A, for patients receiving 25 mg BID or 50 mg BID lonafarnib in combination with 100 mg BID ritonavir, with or without pegylated interferon-α, when HDV RNA viral load was measured after 4 weeks, Comparable viral load reductions were observed compared to patients receiving higher doses in lonafarnib-ritonavir co-treatment. As shown in FIG. 15B, for patients receiving 25 mg BID or 50 BID lonafarnib in combination with 100 mg BID ritonavir, with or without pegylated interferon-α, when HDV RNA viral load was measured after 8 weeks, Comparable viral loads were observed compared to patients receiving higher doses in lonafarnib-ritonavir co-treatment.

Figure 16 shows that a rapid reduction in HDV viral levels was observed in patients receiving 25 mg BID or 50 mg BID lonafarnib in combination with 100 mg BID ritonavir with or without pegylated interferon-α. In addition, for patients who received 50 mg BID lonafarnib in combination with 100 mg BID ritonavir and 50 mg BID lonafarnib in combination with 100 mg BID ritonavir and 180 mcg QW PEG IFN-a, the HDV RNA viral load after 8 weeks was The change in HDV RNA viral load after 48 weeks of treatment with 180 mcg QW PEG IFN-α in combination was comparable. In addition, for a subset of patients receiving 50 mg BID lonafarnib in combination with 100 mg BID ritonavir, 50 mg BID lonafarnib in combination with 100 mg BID ritonavir and 180 mcg QW PEG IFN-a, or 25 mg BID lonafarnib in combination with 100 mg BID ritonavir and 180 mcg QW PEG IFN-α, HDV RNA Virus negativity (clearance) was observed. See FIGS. 17 and 18.

For the group of patients receiving 50 mg BID lonafarnib in combination with 100 mg BID ritonavir, patients 2, 3, 4 and 5 had baseline-to-Nadia quantitative serum HDV RNA levels ≥ 0.5 log HDV RNA copies/mL during active treatment were responsive to treatment, as defined by a decrease in See Figure 17, which shows the time course of HDVIU/mL over 12 weeks of treatment.

For the group of patients receiving 50 mg BID lonafarnib in combination with 100 mg BID ritonavir and 180 mcg QW PEG IFN-α, patients 7 and 8 had quantitative serum HDV RNA levels from baseline to Nadia during active treatment of 0.5 log HDV RNA copies/ Responded to treatment as defined by a drop of ≥ mL. See Figure 18, which shows the time course of HDVIU/mL over 32 weeks of treatment.

For the group of patients receiving 25 mg BID lonafarnib in combination with 100 mg BID ritonavir, patients 9, 10, 11, 12, 13 and 14 had quantitative serum HDV RNA levels from baseline to Nadia 0.5 log HDV RNA during active treatment. Responded to treatment as defined by a decrease of ≥ copies/mL. See Figure 19, which shows the time course of logHDVIU/mL over 8 weeks of treatment.

For the group of patients receiving 25 mg BID lonafarnib in combination with 100 mg BID ritonavir and 180 mcg QW PEG IFN-α, patients 15, 16, 17, 19 and 20 had quantitative serum HDV RNA levels from baseline to Nadia during active treatment. Responsive to treatment, as defined by a decrease of 0.5 log HDV RNA copies/mL or greater. See Figure 20, which shows the time course of logHDVIU/mL over 20 weeks of treatment.

In addition, normalization of ALT values was observed in 65% of patients at 12 weeks. As shown in Figure 21, 17 patients had elevated ALT values at baseline, but only 6 patients had elevated ALT values at 12 weeks. The upper limit of normal for ALT values was 45 in men and 34 in women.

Dosing regimens with lower dosages are also better tolerated, as shown in Table 16 below. Numbers in the table indicate the number of patients experiencing adverse events. Mostly grade 1 gastrointestinal AEs were observed at low doses.

Example 13. Lonafarnib-ritonavir co-treatment period study This example is of three doses (50 mg, 75 mg and 100 mg) of lonafarnib administered once daily in combination with ritonavir each administered once daily for 12 or 24 weeks. Demonstrate efficacy and tolerability. Twenty-one patients with chronic HDV infection were randomized to one of six treatment groups, as outlined in Table 17 below:

Lonafarnib/ritonavir co-treatment is expected to produce a 2-log mean HDV-RNA reduction after 12 weeks of co-treatment. Doses of 50 mg QD lonafarnib combined with 100 mg QD ritonavir and 75 mg QD lonafarnib combined with 100 mg QD ritonavir are expected to be well tolerated to allow dosing for over 24 weeks. . Addition of interferon (eg, pegylated interferon alpha or pegylated interferon lambda) beyond 24 weeks is expected to achieve HDV-RNA negativity in a subset of patients.

Example 14. Lonafarnib-Ritonavir Co-Treatment Dose-Finding Study This example demonstrates the efficacy, safety and tolerability of lonafarnib and ritonavir co-treatment administered twice daily. Fifteen patients (11 men) were enrolled in a 24-week open-label study with the option of dose escalation at the discretion of the investigator. The study was a phase 2 study of 24 weeks of treatment with a titrating regimen of lonafarnib/ritonavir in patients chronically infected with HDV. Lonafarnib was administered starting at 50 mg BID, up to 75 mg BID, then up to 100 mg BID, as tolerated, in combination with ritonavir administered at 100 mg BID. Initial doses of lonafarnib (50 mg BID) and ritonavir (100 mg BID) were maintained for at least 4 weeks. Subsequent dose escalation occurred at intervals of two weeks or longer after the patient first received the specified dose.

At baseline (BL), patients had a mean HDV RNA viral load of 6.53 log ₁₀ IU/mL (range 4.43-8.31 log ₁₀ IU/mL). The mean serum ALT level was 111 U/L (range 53-362 U/L). Liver stiffness (fibrosis) was also assessed by FibroScan®. Two patients had cirrhosis on biopsy. Eleven patients received nucleosides or nucleotide analogues (NUCs) for BL.

By week 8 of treatment, 10 of 15 patients (66%) were able to dose escalate to 100 mg BID lonafarnib in combination with ritonavir. All patients showed a reduction in HDV RNA viral load with a mean reduction from BL of 1.87 log ₁₀ IU/mL (range 0.88-3.13 log ₁₀ IU/mL) to week 8. Three patients showed HBV DNA rebound associated with HDV RNA reduction and two patients started treatment with the anti-HBV drug tenofovir. AEs were primarily grade 1-2 intermittent diarrhea. Three patients had grade 3 AEs (2 diarrhea, 1 asthenia), all transient and non-recurrent. No patient had grade 4 AEs. This data from 8 weeks of treatment indicates that dose escalation of lonafarnib in combination with ritonavir is feasible and leads to early decline of HDV RNA in all patients. Decrease in HDV RNA is associated with rebound of HBV DNA in patients not undergoing NUC, suggesting a suppressive effect of HDV on HBV replication. These data support the use of longer treatment durations.

A schematic of the titration regimen for 24 weeks of treatment is shown in FIG. As shown in Figure 22, after 24 weeks of treatment, 5 of 15 patients (33%) remained on the 100 mg BID lonafarnib combination until 24 weeks (EOT). Patients maintained on a dose of 100 mg BID lonafarnib in combination with ritonavir showed a mean reduction in HDV RNA viral load of 2.9 log ₁₀ IU/mL from BL to week 24. See FIG. Of these 5 patients, 1 patient (patient 3) achieved HDV-RNA negativity at 24 weeks and 1 patient had an HDV-RNA viral load of 32 IU/mL at 24 weeks (i.e., 1 .5 log ₁₀ IU/mL) (lower limit of detection is 14 IU/mL). See FIG.

Of the 10 patients who were dose escalated to ritonavir 100 mg BID lonafarnib by 8 weeks of treatment, 5 patients were tapered to lower doses. See FIG. These patients had less reduction in HDV-RNA viral load than patients who maintained a dose of 100 mg BID lonafarnib in combination with ritonavir through 24 weeks. The remaining 5 patients received "partial" dose escalation from 50 mg BID lonafarnib in combination with ritonavir (patients were unsuccessfully titrated to 100 mg lonafarnib BID) or no dose escalation and had a mean HDV It showed a reduction in RNA viral load from BL to 2.3 log ₁₀ IU/mL at 24 weeks.

Normalization of ALT values was observed in 53% of patients at 24 weeks. As shown in Figure 25, at baseline all 15 patients had elevated ALT values, but at 24 weeks only 7 patients had elevated ALT values. Patients experienced primarily grade 1-2 GI adverse events, as shown in Table 18 below. Table 18 shows the number of patients experiencing a particular grade of AE at least once during the 24-week study. The most common AE was grade 1-2 intermittent diarrhea. No grade 4 AEs were observed.

Example 15. Induction of post-treatment ALT flare with lonafarnib therapy and its therapeutic effects. In some cases, 27 individuals with detectable HDV RNA after receiving lonafarnib at various doses of lonafarnib in combination with ritonavir and/or pegylated interferon-alpha for 12 or 24 weeks Patients were analyzed. A post-treatment ALT flare was defined as an increase in ALT greater than twice the baseline ALT level.

To date, 5 of 27 patients (18.5%) tested have experienced post-procedure ALT flares. These post-treatment flares (median ALT 190 U/L, range 110-1355 U/L) resulted in ALT normalization and HDV RNA negativity within 12-24 weeks. These five patients came from the following lonafarnib-treated cohorts:
Patient A-001-5. BID lonafarnib 200 mg for 12 weeks (Figure 26);
Patient A-001-1. BID lonafarnib 300 mg for 12 weeks (Figure 27);
Patient A-002-3. BID lonafarnib 100 mg in combination with 50 mg BID ritonavir for 12 weeks (Figure 28);
Patient A-002-14. BID lonafarnib 75 mg in combination with 100 mg BID ritonavir for 12 weeks, followed by the addition of pegylated interferon-alpha for 12 weeks (Figure 29); combined BID lonafarnib 50 mg administration (Figure 30);

One patient (patient A-002-3) cleared HBV DNA followed by HBsAg. See FIG. Two other patients (patient A-001-5 and patient A-002-23) showed a 2 log or greater reduction in HBV DNA. See FIGS. 26 and 30. All five patients showed a rapid initial decline in HDV RNA at initiation of lonafarnib treatment. These rapid initial declines were followed by gradual increases upon treatment for reduced lonafarnib exposure (due to dose reduction or excessive GI side effects).

As shown in Figure 26 for patient A-001-5, a 12-week course of treatment with lonafarnib (200 mg BID) resulted in suppression of ALT flare and HDV RNA to undetectable levels. The subsequent rise in HDV viral load (at about week 50) was suppressed by a second course of treatment with lonafarnib (50 mg BID) and ritonavir (100 mg BID). As shown in Figure 26, HDV became undetectable in this patient and the patient remained apparently virus-free when measured at 132 weeks. Surprisingly, HBV VL (ie, HBV DNA level) was also suppressed from a baseline of about 4 log IU/mL to about 1.5 log IU/mL (ie, below LOQ). See FIG.

As shown in FIG. 27 for patient A-001-1, a 12-week course of treatment with lonafarnib (300 mg BID) resulted in approximately 3 log or less suppression of ALT flare and HDV RNA (30-54 weeks). A rise in HDV VL was observed (eg, 78 weeks), which was suppressed by a second course of treatment with low-dose lonafarnib treatment (50 mg BID) and ritonavir (100 mg BID). The transient elevation of HBV DNA levels was also suppressed after ALT flare. The patient remained apparently virus-free when measured at 125 weeks.

As shown in FIG. 28 for patient A-002-3, treatment with lonafarnib (100 mg BID) and ritonavir (50 mg BID) for approximately 10 weeks followed by 2 weeks with lonafarnib (150 mg QD) and ritonavir (50 mg BID) reduced ALT flare. occured. HDV RNA and HBV DNA levels were reduced to undetectable levels. The patient remained apparently virus-free when measured at 95 weeks.

As shown in FIG. 29 for patient A-002-14, a 24-week course of treatment with lonafarnib, ritonavir and pegylated interferon-alpha showed ALT flare, and assay quantitation from greater than 6 log IU/mL, as shown in the figure. Suppression of HDV RNA VL to below the limit (ie, below 3.2 log IU/mL) resulted.

As shown in FIG. 30 for patient A-002-23, a 24-week course of treatment with lonafarnib (50 mg BID) and ritonavir (100 mg BID) resulted in ALT flares and suppression of HDV RNA to approximately 0 log IU/mL.

The data presented here suggest that a short course of lonafarnib may contribute to the effective resetting and activation of the immune response in chronic hepatitis delta, which surprisingly, several In either case, it can spread to HBV. Thus, there appear to be at least two pathways to achieve HDV negativity with lonafarnib treatment. First, lonafarnib-induced progressive suppression of HDV negativity (a more classical antiviral approach) due to ALT normalization during the course of treatment, and second, lonafarnib, which occurs after treatment and results in HDV clearance. Evoked anti-HDV ALT flare.

Example 16. Preparation of lonafarnib-ritonavir-copolymer composition (A) 1:1:2 coprecipitate 5.0 grams of ritonavir, 5.47 grams of lonafarnib, and 10.0 grams of povidone K30 in 600 mL of dichloromethane stirred at room temperature and dissolved. This solution was spray dried using a Model GB22 Yamato Lab spray dryer with the following operating parameters: internal nozzle diameter 711 μm; pump speed 12-14 mL/min; inlet temperature 60° C.; outlet temperature NMT 45° C.; 0.15 MPa and an air flow of 0.5 m ³ /min. Of the 20.47 g solids in the spray solution, 15.9 g were collected in the receiving flask for a yield of 77%. The total solids content in the spray solution was 3% (w/v).

(B) 1:2:3 coprecipitate 6.5 grams of (A) (corresponding to 1.6 grams of ritonavir, 1.6 grams of lonafarnib, and 3.3 grams of povidone K30) of ritonavir-lonafarnib -providone (1:1:2) coprecipitate, an additional 1.6 grams of ritonavir (total amount of ritonavir is 3.2 grams), and an additional 1.5 grams of povidone K30 (of povidone K30) total amount of 4.8 grams) was dissolved in 300 mL of dichloromethane with stirring at room temperature. This solution was spray dried using a Model GB22 Yamato Lab spray dryer with the following operating parameters: internal nozzle diameter 711 μm; pump speed 12-14 mL/min; inlet temperature 60° C.; outlet temperature NMT 45° C.; 0.15 MPa and an air flow of 0.5 m ³ /min. Of the 9.6 g solids in the spray solution, 5.6 g were collected in the receiving flask for a yield of 58%. The total solids content in the spray solution was 3% (w/v).

(C) 1:1:5 coprecipitate 7.5 grams of (A) (corresponding to 1.9 grams of ritonavir, 1.9 grams of lonafarnib, and 3.8 grams of povidone K30) of ritonavir-lonafarnib -Providone (1:1:2) co-precipitate and additional 5.0 grams of Povidone K30 (total of Povidone K30 is 8.8 grams) were dissolved in 390 mL of dichloromethane with stirring at room temperature . This solution was spray dried using a Model GB22 Yamato Lab spray dryer with the following operating parameters: internal nozzle diameter 711 μm; pump speed 12-14 mL/min; inlet temperature 60° C.; outlet temperature NMT 45° C.; 0.15 MPa and an air flow of 0.5 m ³ /min. Of the 12.5 g solids in the spray solution, 8.8 g were collected in the receiving flask for a yield of 70%. The total solids content in the spray solution was 3% (w/v).

(D) 1:1:2 coprecipitate with HPMC polymer 2.5 grams of ritonavir, 2.61 grams of lonafarnib, and 5.0 grams of hydroxymethylcellulose (HPMC) were stirred in 340 mL of dichloromethane at room temperature. Dissolved. This solution was spray dried using a Model GB22 Yamato Lab spray dryer with the following operating parameters: internal nozzle diameter 711 μm; pump speed 12-14 mL/min; inlet temperature 60° C.; outlet temperature NMT 45° C.; 0.15 MPa and an air flow of 0.5 m ³ /min. Of the 10.1 g solids in the spray solution, 7.2 g were collected in the receiving flask for a yield of 71%. The total solids content in the spray solution was 3% (w/v).

Analysis of lonafarnib-ritonavir-copolymer compositions X-ray powder diffraction (XRPD) confirmed the amorphous state of each coprecipitate of (A)-(D). Diffraction patterns were confirmed by X-ray diffraction using a Bruker D2 Phaser X-ray diffractometer equipped with a Lynxeye detector, CuKα radiation (λ=1.5406 Å). Acquisitions were performed over a range of 5-55 degrees 2-theta, increments of 0.05 degrees 2-theta, a step time of 1.0 sec, and an aperture slit of 0.6 mm and a detection window of 2.5 mm. Samples were analyzed using a low volume sample holder and kept under constant rotation of 15 rpm during analysis. FIG. 31 is a powder X-ray pattern of amorphous 1:1:2, 1:2:3, and 1:1:5 ritonavir-lonafarnib-copolymer coprecipitates with povidone as a copolymer. Consistent with the properties of amorphous solid forms, the amorphous 1:1:2, 1:2:3, and 1:1:5 coprecipitates do not exhibit crystalline diffraction peaks. Amorphous 1:1:2 co-precipitates with HPMC also show no crystalline diffraction peaks (data not shown).

Residual solvent from the spray-dried material was confirmed by thermogravimetric analysis (TGA). Analysis was performed using a TA Instrument Q50 thermogravimetric analyzer over a temperature range of 25°C to 200°C with a scan rate of 10°C/min. Samples were heated in platinum open pans under a nitrogen purge (60 mL/min).

FIG. 32A shows sample weight (percentage of original weight) as a function of temperature. This material showed a distinct weight loss phase. The first step (4.8-5.6% weight loss) at a temperature of 25-100°C is the loss of volatile compounds (water and dichloromethane) followed by material decomposition starting at about 180°C. handle. Identification and quantification of residual solvents using more sophisticated techniques should be employed to ensure compliance with ICH Q3C guidelines.

FIG. 32B shows samples with similar API (active pharmaceutical ingredient) composition but different polymers, 1:1:2 ritonavir-lonafarnib-povidone containing sample and 1:1:2 ritonavir-lonafarnib-HPMC containing Compare the samples. As shown in Figure 23B, the HPMC-containing sample contained 1.7% volatiles, which is much lower compared to the povidone-containing sample's 4.8%. This difference is believed to be related to the higher hygroscopicity and/or affinity for dichloromethane of povidone versus HPMC.

Example 17 Exemplary Co-Therapy Doses By way of illustration and not limitation, this example provides exemplary doses of lonafarnib-ritonavir co-therapy and lonafarnib-interferon lambda co-therapy. For lonafarnib-ritonavir co-treatment, exemplary doses include the following combinations (see Table 19): L1+(R1 or R2 or R3), where L1 and R are from the same row.

For lonafarnib-interferon lambda co-treatment, exemplary doses include, by way of example and not limitation, the following combinations (see Table 20):

All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent was specifically and individually indicated to be incorporated by reference, and , are incorporated herein by reference to disclose and describe the methods and/or materials with which the publications are cited.

Although the present invention is specifically disclosed in terms of certain aspects, embodiments and optional features, alterations, modifications and variations of such aspects, embodiments and optional features will occur to those skilled in the art. and that such modifications, improvements and variations are considered to be within the scope of the present disclosure.

The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. Also, where features or aspects of the invention are described with respect to the Markush group, those skilled in the art will recognize that the invention thereby also relates to any individual member or subgroup of members of the Markush group. Will.
The present disclosure includes the following aspects and embodiments.
[1]
A method of reducing HDV viral load in a human patient with hepatitis delta virus (HDV) infection comprising treating the patient with lonafarnib-ritonavir co-therapy for at least 30 days, wherein the patient has at least A method wherein having a baseline viral load of 10 ⁵ IU/mL serum and treatment results in a reduction in viral load to less than 10 ³ IU/mL serum.
[2]
The method of [1], wherein the HDV viral load remains below 10 ³ IU/mL serum for at least 1 month after treatment .
[3]
The method of [1], wherein the treatment results in an HDV viral load below the level of detection.
[4]
The method of [3], wherein the HDV viral load remains below the level of detection for at least one month after treatment.
[5]
The method of [1], wherein treatment with lonafarnib-ritonavir cotherapy is continued for at least 30 days after the patient is determined to have a viral load of less than 10 3 HDV RNA copies per mL of serum ^.
[6]
The method of any one of [1]-[5]], wherein lonafarnib is administered at a dose of 25 mg BID and ritonavir is administered at a dose of 100 mg BID.
[7]
The method of any one of [1]-[6], wherein the patient is treated with lonafarnib-ritonavir co-therapy for at least 60 days.
[8]
The method of [7], wherein the patient is treated with lonafarnib-ritonavir co-therapy for at least 90 days.
[9]
Any one of [1] to [8], comprising administering lonafarnib at a first dose followed by administering lonafarnib at a second dose, wherein the second dose is lower than the first dose the method of.
[10]
The method of any one of [1]-[9], comprising detecting the occurrence of hepatitis flare.
[11]
The method of [10], wherein the hepatitis flare is characterized by an acute elevation of serum alanine aminotransferase (ALT) to levels above 200 U/L.
[12]
The method of any one of [1]-[11], comprising detecting a transient increase of at least 3 logs in the patient's hepatitis B virus (HBV) viral load.
[13]
The method of any one of [10]-[12], wherein the lonafarnib-ritonavir co-treatment is discontinued prior to detecting the development of a hepatitis flare or prior to detecting a transient increase.
[14]
A method of inducing immune reactivation in patients infected with hepatitis delta virus (HDV) and hepatitis B virus (HBV) comprising lonafarnib-ritonavir co-administration for at least 12 weeks and/or until hepatitis flare is observed. A method comprising administering a treatment wherein lonafarnib is administered in a total daily dose ranging from 50 mg to 150 mg and ritonavir is administered in a total daily dose ranging from 100 mg to 200 mg.
[15]
The method of any one of [1]-[14], wherein the lonafarnib-ritonavir co-therapy is discontinued after 10-24 weeks of treatment and the lonafarnib-ritonavir co-therapy is not administered to the patient for at least 4 weeks.
[16]
The method of [15], wherein the lonafarnib-ritonavir co-treatment is discontinued after 10-14 weeks of treatment.
[17]
The method of [16], wherein the lonafarnib-ritonavir co-treatment is discontinued after 12 weeks of treatment.
[18]
The method of any one of [14]-[17], wherein the hepatitis flare is characterized by an acute elevation of serum alanine aminotransferase (ALT) to levels above 200 U/L.
[19]
The method of any one of [14]-[18], wherein the hepatitis flare is accompanied by a transient increase in the patient's HBV viral load.
[20]
The method of any one of [14]-[19], wherein HDV viral load is reduced by at least 3 logs after immune reactivation.
[21]
The method of any one of [14]-[20], wherein HBV viral load is reduced by at least 2 logs after immune reactivation.
[22]
The method of [20] or [21], wherein the HDV viral load and/or HBV viral load is reduced to undetectable levels.
[23]
Inducing immune reactivation in patients infected with HDV and HBV comprises administering lonafarnib at a first dose followed by administering lonafarnib at a second dose, wherein the second dose is The method of any one of [14]-[22], wherein the dose is lower than the dose of
[24]
The method of [23], wherein the first dose is administered for at least 8 weeks and the second dose is administered for at least 2 weeks, and optionally at least 4 weeks.
[25]
The method of [23] or [24], wherein the first dose of lonafarnib is 50 mg BID and the second dose of lonafarnib is 50 mg QD.
[26]
The method of [25], wherein the first dose of lonafarnib and the second dose of lonafarnib are administered in combination with ritonavir at a dose of 100 mg BID.
[27]
Any one of [1]-[26], wherein the patient has chronic HBV infection and the course of treatment results in a decrease in the patient's HBV viral load compared to baseline levels at the start of treatment. described method.
[28]
A method of reducing HBV viral load in a patient infected with HBV and HDV comprising administering lonafarnib at a total daily dose ranging from 50 mg to 150 mg for at least 12 weeks and detecting at least a 1 log reduction in HBV viral load. method, including
[29]
The method of [28], comprising administering lonafarnib and ritonavir.
[30]
The method of [28] or [29], wherein the patient has not been treated with antiviral nucleotides or nucleoside analogues.
[31]
The method of any one of [28]-[30], wherein the treatment results in at least a 2-log reduction in HBV viral load.
[32]
The method of any one of [1]-[31], further comprising administering interferon to the patient.
[33]
The method of [32], wherein the interferon is pegylated interferon lambda.
[34]
The method of [32] or [33], wherein interferon is administered at a dose of 120 mcg QW or 180 mcg QW.
[35]
A method of reducing the viral load of hepatitis delta virus (HDV) in a human patient with chronic HDV infection, the method comprising treating the patient with lonafarnib-interferon co-therapy for at least 30 days, wherein the co-treatment is 50 mg. A method comprising orally administering lonafarnib with a total daily dose ranging from ˜150 mg and orally administering interferon lambda-1a with a total weekly dose ranging from 120 mcg to 180 mcg.
[36]
The method of [35], wherein the interferon lambda-1a is pegylated interferon lambda-1a.
[37]
The method of [35] or [36], wherein lonafarnib is administered at a dose of 25 mg BID.
[38]
The method of [35] or [36], wherein lonafarnib is administered at a dose of 50 mg BID.
[39]
The method of any one of [1]-[38], wherein the treatment results in improvement of the patient's liver function.
[40]
The improved liver function is an improvement in one or more liver function parameters selected from the group consisting of serum albumin levels, bilirubin levels, alanine aminotransferase (ALT) levels, aspartate aminotransferase (AST) levels, and prothrombin activity. The method of [39], wherein
[41]
The method of [39] or [40], wherein treatment results in an improvement in one or more liver function parameters to levels characteristic of healthy subjects not infected with HDV or hepatitis B virus (HBV). .
[42]
The method of any one of [1]-[38], wherein the treatment delays the patient's need for liver transplantation.
[43]
A unit dosage form comprising lonafarnib and ritonavir, wherein the lonafarnib and ritonavir are present in a ratio of about 1:2 (w/w) or about 1:4 (w/w), the unit dosage form for oral administration Formulated, unit dosage form.
[44]
The unit dosage form of [43], comprising lonafarnib in an amount of about 25 mg to about 100 mg and ritonavir in an amount of about 50 mg to about 100 mg.
[45]
The unit dosage form of [43] or [44], comprising a mixture, multiparticulate formulation, or bilayer formulation of lonafarnib and ritonavir.
[46]
The unit dosage form of any one of [43]-[45], formulated as a capsule or tablet.
[47]
The unit dosage form of any one of [43]-[46], wherein one or both of lonafarnib and ritonavir are formulated for immediate release.
[48]
The unit dosage form of any one of [43]-[46], wherein one or both of lonafarnib and ritonavir are formulated for controlled release.
[49]
A liquid formulation comprising lonafarnib and ritonavir in a 1:4 or 1:2 ratio.

Claims (34)

A medicament comprising lonafarnib and ritonavir for reducing HDV viral load in a human patient with hepatitis delta virus (HDV) infection, wherein lonafarnib and ritonavir are administered as lonafarnib-ritonavir co-therapy for at least 12 weeks, Patients were treated and had a baseline viral load of at least 10 ⁵ IU/mL serum prior to initiation of treatment, treatment resulted in a decrease in viral load to less than 10 ³ IU/mL serum, and lonafarnib , a medicament administered in a total daily dose ranging from 50 mg to 150 mg. 2. A medicament according to claim 1, wherein the HDV viral load remains below 10 ^<3> IU/mL serum for at least one month after treatment. 2. A medicament according to claim 1, wherein the treatment results in an HDV viral load below the level of detection. 4. A medicament according to claim 3, wherein the HDV viral load remains below the level of detection for at least one month after treatment. 2. The medicament of claim 1, wherein treatment with lonafarnib-ritonavir co-therapy is continued for at least 30 days after the patient is determined to have a viral load of less than 10 ³ HDV RNA copies per mL of serum. A medicament according to any one of claims 1 to 5, wherein lonafarnib is administered at a dose of 25 mg BID and ritonavir is administered at a dose of 100 mg BID. A medicament according to any one of claims 1 to 6, wherein the patient is treated with lonafarnib-ritonavir co-therapy for at least 120 days. 8. The medicament according to claim 7, wherein the patient is treated with lonafarnib-ritonavir co-therapy for at least 180 days. A medicament according to any one of claims 1 to 8, wherein a first dose of lonafarnib is administered followed by a second dose of lonafarnib, the second dose being lower than the first dose. The medicament according to any one of claims 1 to 9, which is administered while detecting the occurrence of hepatitis flare. 11. A medicament according to claim 10, wherein the hepatitis flare is characterized by an acute elevation of serum alanine aminotransferase (ALT) to levels above 200 U/L. 10. The patient is also infected with hepatitis B virus (HBV), and the medicament is administered while detecting a transient increase of at least 3 logs in the patient's hepatitis B virus (HBV) viral load. The medicament according to any one of 1 to 11. The medicament according to any one of claims 10-12, wherein the lonafarnib-ritonavir co-treatment is discontinued before detecting the development of hepatitis flares or before detecting a transient increase. A medicament comprising lonafarnib and ritonavir for inducing immune reactivation in patients infected with hepatitis delta virus (HDV) and hepatitis B virus (HBV), wherein lonafarnib and ritonavir are administered for at least 12 weeks and/or or as lonafarnib-ritonavir co-treatment, with lonafarnib administered at a total daily dose ranging from 50 mg to 150 mg and ritonavir at a total daily dose ranging from 100 mg to 200 mg until hepatitis flare is observed. medicine. The medicament according to any one of claims 1 to 14, wherein the lonafarnib-ritonavir co-therapy is discontinued after 10-24 weeks of treatment and the lonafarnib-ritonavir co-therapy is not administered to the patient for at least 4 weeks. A medicament according to claim 15, wherein the lonafarnib-ritonavir co-treatment is discontinued after 10-14 weeks of treatment. 17. A medicament according to claim 16, wherein the lonafarnib-ritonavir co-treatment is discontinued after 12 weeks of treatment. A medicament according to any one of claims 14 to 17, wherein the hepatitis flare is characterized by an acute elevation of serum alanine aminotransferase (ALT) to levels above 200 U/L. The medicament according to any one of claims 14-18, wherein the hepatitis flare is accompanied by a transient increase in the patient's HBV viral load. A medicament according to any one of claims 14 to 19, wherein the HDV viral load is reduced by at least 3 logs after immune reactivation. A medicament according to any one of claims 14 to 20, wherein the HBV viral load is reduced by at least 2 logs after immune reactivation. 22. A medicament according to claim 20 or 21, wherein the HDV viral load and/or the HBV viral load is reduced to undetectable levels. in inducing immune reactivation in a patient infected with HDV and HBV, administering lonafarnib at a first dose followed by administering lonafarnib at a second dose, wherein the second dose is lower than the first dose; The medicament according to any one of claims 14-22. 24. A medicament according to claim 23, wherein the first dose is administered for at least 8 weeks and the second dose is administered for at least 2 weeks and optionally at least 4 weeks. 25. The medicament according to claim 23 or 24, wherein the first dose of lonafarnib is 50 mg BID and the second dose of lonafarnib is 50 mg QD. 26. The medicament of claim 25, wherein the first dose of lonafarnib and the second dose of lonafarnib are administered in combination with ritonavir at a dose of 100 mg BID. 27. Any one of claims 1-26, wherein the patient has a chronic HBV infection and the course of treatment results in a decrease in the patient's HBV viral load compared to baseline levels at the start of treatment. Medicine. A medicament comprising lonafarnib for reducing HBV viral load in patients infected with HBV and HDV, wherein lonafarnib is administered at a total daily dose ranging from 50 mg to 150 mg for at least 12 weeks, and wherein the HBV viral load is reduced to at least A drug in which a 1 log reduction is detected. 29. A medicament according to claim 28, wherein the patient is also administered ritonavir. 30. A medicament according to claim 28 or 29, wherein the patient has not been treated with antiviral nucleotides or nucleoside analogues. A medicament according to any one of claims 28-30, wherein the treatment results in at least a 2-log reduction in HBV viral load. A medicament according to any one of claims 1 to 31, wherein the patient is also administered interferon. 33. A medicament according to claim 32, wherein the interferon is pegylated interferon lambda. 34. A medicament according to claim 32 or 33, wherein the interferon is administered at a dose of 120mcgQW or 180mcgQW.

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